Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors

ABSTRACT

Provided herein are compounds of the Formula I: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1 , X 2 , X 3 , X 4 , Ring D, E, R a , R b , n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/860,894, filed Jan. 3, 2018, which is a continuation of U.S.application Ser. No. 15/858,929, filed Dec. 29, 2017, which is acontinuation of International Application No. PCT/US2017/055993, filedOct. 10, 2017, which claims priority to U.S. Provisional ApplicationSer. No. 62/566,030, filed Sep. 29, 2017; 62/531,690, filed Jul. 12,2017; 62/491,180, filed Apr. 27, 2017; 62/447,849, filed Jan. 18, 2017;and 62/406,275, filed Oct. 10, 2016, each of which is incorporated byreference in its entirety herein.

BACKGROUND

The present disclosure relates to novel compounds which exhibitRearranged during Transfection (RET) kinase inhibition, pharmaceuticalcompositions comprising the compounds, processes for making thecompounds, and the use of the compounds in therapy. More particularly,it relates to substituted pyrazolo[1,5-a]pyridine compounds useful inthe treatment and prevention of diseases which can be treated with a RETkinase inhibitor, including RET-associated diseases and disorders.

RET is a single-pass transmembrane receptor belonging to the tyrosinekinase superfamily that is required for normal development, maturationand maintenance of several tissues and cell types (Mulligan, L. M.,Nature Reviews Cancer, 2014, 14, 173-186). The extracellular portion ofthe RET kinase contains four calcium-dependent cadherin-like repeatsinvolved in ligand binding and a juxtamembrane cysteine-rich regionnecessary for the correct folding of the RET extracellular domain, whilethe cytoplasmic portion of the receptor includes two tyrosine kinasesubdomains.

RET signaling is mediated by the binding of a group of soluble proteinsof the glial cell line-derived neurotrophic factor (GDNF) family ligands(GFLs), which also includes neurturin (NTRN), artemin (ARTN) andpersephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev., 2005, 16,441-67). Unlike other receptor tyrosine kinases, RET does not directlybind to GFLs and requires an additional co-receptor: that is, one offour GDNF family receptor-α (GFRα) family members, which are tethered tothe cell surface by a glycosylphosphatidylinositol linkage. GFLs andGFRα family members form binary complexes that in turn bind to RET andrecruit it into cholesterol-rich membrane subdomains, which are known aslipid rafts, where RET signaling occurs.

Upon binding of the ligand-co-receptor complex, RET dimerization andautophosphorylation on intracellular tyrosine residues recruits adaptorand signaling proteins to stimulate multiple downstream pathways.Adaptor protein binding to these docking sites leads to activation ofRas-MAPK and PI3K-Akt/mTOR signaling pathways or to recruitment of theCBL family of ubiquitin ligases that functions in RET downregulation ofthe RET-mediated functions.

Aberrant RET expression and/or activity have been demonstrated indifferent cancers and in gastrointestinal disorders such as irritablebowel syndrome (IBS).

SUMMARY OF THE INVENTION

It has now been found that substituted pyrazolo[1,5-a]pyridine compoundsare inhibitors of RET kinase, and are useful for treating diseases suchas proliferative diseases such as cancers.

Accordingly, provided herein is a compound of the Formula I:

or pharmaceutically acceptable salt or solvate thereof, wherein A, B,X¹, X², X³, X⁴, Ring D, E, R^(a), R^(b), n and m are as defined herein.

Also provided herein is a pharmaceutical composition comprising acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, in admixture with a pharmaceutically acceptable diluent orcarrier.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein.

Also provided herein is a method of treating a RET-associated disease ordisorder in a patient in need of such treatment, the method comprisingadministering to the patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof as defined herein.

Also provided herein is a method of treating cancer and/or inhibitingmetastasis associated with a particular cancer in a patient in need ofsuch treatment, the method comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein.

Also provided herein is a method of treating irritable bowel syndrome(IBS) and/or pain associated with IBS in a patient in need of suchtreatment, the method comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein.

Also provided is a method of providing supportive care to a cancerpatient, including preventing or minimizing gastrointestinal disorders,such as diarrhea, associated with treatment, including chemotherapeutictreatment, the method comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein for use in therapy.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein for use in the treatment of cancer and/orinhibiting metastasis associated with a particular cancer.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein for use in the treatment of irritable bowelsyndrome (IBS) or pain associated with IBS.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein for use providing supportive care to a cancerpatient, including preventing or minimizing gastrointestinal disorders,such as diarrhea, associated with treatment, including chemotherapeutictreatment.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof for use in the inhibition of RETkinase activity.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein, for use in the treatment of a RET-associateddisease or disorder.

Also provided herein is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the treatment of cancer and/orinhibiting metastasis associated with a particular cancer.

Also provided herein is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the treatment of irritable bowelsyndrome (IBS) or pain associated with IBS.

Also provided herein is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for providing supportive care to acancer patient, including preventing or minimizing gastrointestinaldisorders, such as diarrhea, associated with treatment, includingchemotherapeutic treatment.

Also provided herein is a use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the inhibition of RET kinaseactivity.

Also provided herein is the use of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, as defined herein,in the manufacture of a medicament for the treatment of a RET-associateddisease or disorder.

Also provided herein is a method for treating cancer in a patient inneed thereof, the method comprising (a) determining if the cancer isassociated with a dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., aRET-associated cancer); and (b) if the cancer is determined to beassociated with a dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., aRET-associated cancer), administering to the patient a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof.

Also provided herein is a pharmaceutical combination for treating cancer(e.g., a RET-associated cancer, such as a RET-associated cancer havingone or more RET inhibitor resistance mutations) in a patient in needthereof, which comprises (a) a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, (b) an additionaltherapeutic agent, and (c) optionally at least one pharmaceuticallyacceptable carrier, wherein the compound of Formula I or thepharmaceutically acceptable salt or solvate thereof and the additionaltherapeutic are formulated as separate compositions or dosages forsimultaneous, separate or sequential use for the treatment of cancer,wherein the amounts of the compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof and of the additional therapeuticagent are together effective in treating the cancer. Also providedherein is a pharmaceutical composition comprising such a combination.Also provided herein is the use of such a combination for thepreparation of a medicament for the treatment of cancer. Also providedherein is a commercial package or product comprising such a combinationas a combined preparation for simultaneous, separate or sequential use;and to a method of treatment of cancer a patient in need thereof.

Also provided herein is a method for reversing or preventing acquiredresistance to an anticancer drug, comprising administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, to a patient atrisk for developing or having acquired resistance to an anticancer drug.In some embodiments, the patient is administered a dose of theanticancer drug (e.g., at substantially the same time as a dose of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof is administered to the patient).

Also provided herein is a method of delaying and/or preventingdevelopment of cancer resistant to an anticancer drug in an individual,comprising administering to the individual an effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, before, during, or after administration of an effective amountof the anticancer drug.

Also provided herein is a method of treating an individual with cancerwho has an increased likelihood of developing resistance to ananticancer drug, comprising administering to the individual (a) aneffective amount of a compound of Formula I before, during, or afteradministration of (b) an effective amount of the anticancer drug.

Also provided are methods of treating an individual with aRET-associated cancer that has one or more RET inhibitor resistancemutations that increase resistance of the cancer to a first RETinhibitor (e.g., a substitution at amino acid position 804, e.g., V804M,V804L, or V804E, and/or one or more RET inhibitor resistance mutationslisted in Tables 3 and 4), that include administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof,before, during, or after administration of another anticancer drug(e.g., a second RET kinase inhibitor).

Also provided are methods of treating an individual with aRET-associated cancer that include administering a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof, before,during, or after administration of another anticancer drug (e.g., afirst RET kinase inhibitor).

Also provided herein is a method for treating irritable bowel syndrome(IBS) in a patient in need thereof, the method comprising (a)determining if the IBS is associated with a dysregulation of a RET gene,a RET kinase, or expression or activity or level of any of the same; and(b) if the IBS is determined to be associated with a dysregulation of aRET gene, a RET kinase, or expression or activity or level of any of thesame, administering to the patient a therapeutically effective amount ofa compound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof.

Also provided herein is a pharmaceutical combination for treatingirritable bowel syndrome (IBS) in a patient in need thereof, whichcomprises administering (a) a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, (b) an additionaltherapeutic agent, and (c) optionally at least one pharmaceuticallyacceptable carrier, for simultaneous, separate or sequential use for thetreatment of IBS, wherein the amounts of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof and of theadditional therapeutic agent are together effective in treating the IBS.Also provided herein is a pharmaceutical composition comprising such acombination. Also provided herein is the use of such a combination forthe preparation of a medicament for the treatment of the IBS. Alsoprovided herein is a commercial package or product comprising such acombination as a combined preparation for simultaneous, separate orsequential use; and to a method of treatment of the IBS a patient inneed thereof.

Also provided herein is a process for preparing a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof obtained by a process of preparingthe compound as defined herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein is a compound of Formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein:

X¹, X², X³ and X⁴ are independently CH, CCH₃, CF or N, wherein zero, oneor two of X¹, X², X³ and X⁴ is N;

A is H, CN, Cl, methyl, ethyl or cyclopropyl;

B is:

(a) hydrogen,

(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,

(f) (R¹R²N)C1-C6 alkyl- where R¹ and R² are independently selected fromH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6 alkoxy)C(═O)—;

(g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andis optionally substituted with one or more independently selected C1-C6alkyl substituents;

(h) (C3-C6 cycloalkyl)C1-C3 alkyl-, wherein said cycloalkyl isoptionally substituted with OH,

(i) (hetCyc^(a))C1-C3 alkyl-,

(j) hetCyc^(a),

(k) (R¹R²N)C(═O)C1-C6 alkyl-, where R¹ and R² are independently selectedfrom H and C1-C6 alkyl;

(l) (R¹R²N)C(═O)—, where R¹ and R² are independently selected from H andC1-C6 alkyl, or

(m) hetCyc^(a)C(═O)C1-C6 alkyl-;

hetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6alkoxy)C(═O)—;

Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen, (ii) a saturated 7-8membered bridged heterocyclic ring having one ring heteroatom which isnitrogen, or (iii) a saturated 7-11 membered heterospirocyclic ringsystem having one ring heteroatom which is nitrogen;

each R^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-;

R^(b) is (a) hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—, (k) hetCyc^(b)C(═O)NH— or (1)hetAr^(a)C(═O)NH—;

hetCyc^(b) is a 4-6 membered heterocyclic ring, a 7-8 membered bridgedheterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinhetCyc^(b) is optionally substituted with one or more substituentsindependently selected from OH, fluoro, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6alkoxy)C(═O)—, C1-C6 alkoxy, and R′R″N— where R′ and R″ areindependently hydrogen or C1-C6 alkyl;

hetAr^(a) is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S wherein hetAr^(a) is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3fluoros),

R^(c) is hydrogen or C1-C6 alkyl;

R^(d) is hydrogen, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂— wherein the phenylis optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-(optionallysubstituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyC1-C6 alkyl,(C1-C6 alkyl)SO₂—, R^(e)R^(f)N— and (R^(e)R^(f)N)C1-C6 alkyl- where eachR^(e) and R^(f) is independently H or C1-C6 alkyl, (C1-C6 alkoxy)C1-C6alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclicring having a ring heteroatom selected from N and O and optionallysubstituted with C1-C6 alkyl;

n is 0, 1, 2, 3, 4, 5 or 6;

m is 0 or 1;

E is:

(a) hydrogen,

(b) hydroxy,

(c) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(d) Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros,

(e) hetAr²C1-C6 alkyl-,

(f) (C1-C6 alkoxy)C1-C6 alkoxy-,

(g) Ar¹O—,

(h) hetAr²—O—,

(i) Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl,

(j) hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl,

(k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl;

(l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H orC1-C6 alkyl,

(n) R⁴R⁵NC(═O)—,

(o) Ar¹NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl,

(p) hetAr²NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl,

(q) Ar¹(C1-C6 alkyl)C(═O)— wherein said alkyl portion is optionallysubstituted with OH, hydroxy(C1-C6 alkyl), C1-C6 alkoxy or NH₂,

(r) hetCyc⁵C(═O)—,

(s) R⁴R⁵NC(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or

(t) (C1-C6 alkyl)SO₂—;

(u) Ar¹(C1-C6 alkyl)C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(v) hetAr⁴C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(w) hetAr²—S(═O)—,

(x) (C3-C6 cycloalkyl)CH₂SO₂—,

(y) Ar¹(C1-C6 alkyl)SO₂—,

(z) hetAr²SO₂—,

(aa) Ar¹,

(bb) hetAr²,

(cc) hetCyc⁵,

(dd) C1-C6 alkoxy,

(ee) Ar¹(C1-C6 alkyl)-O—,

(ff) hetAr²(C1-C6 alkyl)-O—,

(gg) hetAr²—O—C1-C6 alkyl-,

(hh) Ar¹(C1-C6 alkyl)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(ii) hetAr²—S—,

(jj) Ar²SO₂NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H or C1-C6alkyl,

(kk) (C1-C6 alkoxy)C(═O)—,

(ll) (C1-C6 alkyl)NR^(g)C(═O)O— where R^(g) is H or C1-C6 alkyl,

(mm) (C1-C6 alkyl)NR^(g)SO₂— where R^(g) is H or C1-C6 alkyl,

(nn) hetCyc⁵C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(oo) Q-NR^(h)(C1-C3 alkyl)C(═O)NR^(g)— where R^(g) and R^(h) areindependently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—,

where R^(g) and R^(h) are independently H or C1-C6 alkyl, Q is H, C1-C6alkyl or (C1-C6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,

where R^(g) and R^(h) are independently H or C1-C6 alkyl and Q is H,C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,

where R^(g) is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—, or

(ss) R^(g)R^(h)N— where R^(g) and R^(h) are independently H or C1-C6alkyl,

(tt) (C3-C6 cycloalkyl)C(═O)NR^(g)— where the cycloalkyl is optionallyand independently substituted with one or more halogens,

(uu) (C1-C6 alkyl)C(═O)NR^(g)CH₂— where R^(g) is H or C1-C6 alkyl, or

(vv) C1-C6 alkyl)SO₂NR^(g)— where R^(g) is H or C1-C6 alkyl;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl,hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO₂—, R^(e)R^(f)N— and(R^(e)R^(f)N)C1-C6 alkyl- where each R^(e) and R^(f) is independently Hor C1-C6 alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S, or a 9-10 membered bicyclicheteroaryl having 1-2 ring nitrogen atoms, wherein hetAr² is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros) and hydroxyC1-C6 alkoxy-;

hetCyc⁵ is a 4-6 membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N, O and S wherein saidheterocyclic ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkoxy and oxo;

R³ is C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6cycloalkyl)CH₂—, (C3-C6 cycloalkyl)O—, (C3-C6 cycloalkyl)CH₂O—,hetCyc⁷O—, Ph-O—, or (C1-C6 alkoxy)C1-C6 alkyl-; wherein each of saidC3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R′R″N—where R′ and R″ are independently hydrogen or C1-C6 alkyl;

R⁴ is H or C1-C6 alkyl;

R⁵ is Ar², hetAr³, Ar²CH₂—, hetCyc⁶-CH₂—, hydroxyC1-C6 alkyl-, (C3-C6cycloalkyl)CH₂—, or C1-C6 alkyl optionally substituted with 1-3 fluoros;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, andR^(g)R^(h)N— where R^(g) and R^(h) are independently H or C1-C6 alkyl,or Ar² is phenyl fused to a 6 membered heterocyclic ring having a ringnitrogen atom and optionally substituted with C1-C6 alkyl;

hetAr³ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and(C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros);

hetAr⁴ is pyridin-4(1H)-onyl or pyridin-2(1H)-onyl optionallysubstituted with one or more substituents independently selected fromC1-C6 alkyl and halogen;

hetCyc⁶ is a 5-7 membered heterocyclic ring having 1-3 ring heteroatomsindependently selected from N, O and S; and

hetCyc⁷ is a 5-7 membered heterocyclic ring having 1-3 ring heteroatomsindependently selected from N, O and S.

For complex chemical names employed herein, a substituent group istypically named before the group to which it attaches. For example,methoxyethyl comprises an ethyl backbone with a methoxy substituent.

The term “halogen” means —F (sometimes referred to herein as “fluoro” or“fluoros”), —Cl, —Br and —I.

The terms “C1-C3 alkyl”, “C3-C6 alkyl”, “C1-C6 alkyl”, and “C2-C6 alkyl”as used herein refer to saturated linear or branched-chain monovalenthydrocarbon radicals of one to three, three to six, one to six, or twoto six carbon atoms, respectively. Examples include, but are not limitedto, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl,tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

The term “C1-C6 alkyl optionally substituted with 1-3 fluoros” as usedherein refers to a C1-C6 alkyl radical as defined herein, wherein one tothree hydrogen atoms is replaced with one to three fluoro atoms,respectively. Examples include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2- and trifluoroethyl.

The term “C1-C6 alkoxy” as used herein refer to saturated linear orbranched-chain monovalent alkoxy radicals of one to six carbon atoms,wherein the radical is on the oxygen atom. Examples include methoxy,ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

The term “(C1-C6 alkoxy)C1-C6 alkyl” as used herein refers to saturatedlinear or branched-chain monovalent radicals of one to six carbon atoms,wherein one of the carbon atoms is substituted with a C1-C6 alkoxy groupas defined herein. Examples include methoxymethyl (CH₃OCH₂—) andmethoxyethyl (CH₃OCH₂CH₂—).

The term “(C1-C6 alkoxy)C1-C6 alkoxy” as used herein refers to a C1-C6alkoxy radical as defined herein, wherein one of the carbon atoms issubstituted with a C1-C6 alkoxy group as defined herein. Examplesinclude methoxymethoxy (CH₃OCH₂O—) and ethoxymethoxy (CH₃CH₂O—CH₂O—).

The terms “hydroxyC1-C6 alkyl” and “hydroxyC2-C6 alkyl”, as used hereinrefers to saturated linear or branched-chain monovalent alkyl radicalsof one to six or two to six carbon atoms, respectively, wherein one ofthe carbon atoms is substituted with a hydroxy group.

The term “dihydroxyC3-C6 alkyl” as used herein refers to a C3-C6 alkylradical as defined herein, wherein two hydrogen atoms are replaced witha hydroxy group, provided the hydroxy groups are not on the same carbon.

The term “(R¹R²N)C1-C6 alkyl” as used herein refers to a C1-C6 alkylradical as defined herein, wherein one of the carbon atoms issubstituted with a R¹R²N— group, wherein R¹ and R² are as definedherein.

The term “hetAr¹C1-C6 alkyl” as used herein refers to a C1-C6 alkylradical as defined herein, wherein one of the carbon atoms issubstituted with a hetAr¹ group, wherein hetAr¹ is as defined herein.

The term “C3-C6 cycloalkyl” as used herein refers to cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

The term “C3-C6 cycloalkylidene ring” as used herein refers to adivalent C3-C6 cycloalkane ring derived from a saturated 3-6 memberedhydrocarbon ring by removal of two hydrogen atoms from the same carbonatom, such as for example, cyclopropylidene, cyclobutylidene,cyclopentylidene, and cyclohexylidene. It can be represented inillustrative fashion by the following structure in which n is 1, 2 or 3:

The term “(C3-C6 cycloalkyl)C1-C3 alkyl” as used herein refers to aC1-C3 alkyl radical as defined herein, wherein one of the carbon atomsis substituted with a C3-C6 cycloalkyl ring. An example iscyclobutylmethyl.

The term “(hetCyc^(a))C1-C3 alkyl” as used herein refers to a C1-C3alkyl radical as defined herein, wherein one of the carbon atoms issubstituted with a hetCyc^(a) group, wherein hetCyc^(a) is as definedherein.

The term “Ar¹C1-C6 alkyl” as used herein refers to a C1-C6 alkyl radicalas defined herein, wherein one of the carbon atoms is substituted withan Ar¹ group, wherein Ar¹ is as defined herein.

The terms “hetAr²C1-C6 alkyl” as used herein refers to a C1-C6 alkylradical as defined herein, wherein one of the carbon atoms issubstituted with a hetAr² group, wherein hetAr² is as defined herein.

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom, i.e., ═O. For example, in one embodiment when referring tohetCyc^(a), a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and substituted with an oxo may be,for example, a pyrrolidinyl ring substituted with oxo (e.g., apyrrolidinonyl ring), which may be represented by the structure:

The term “spirocyclic ring” as used herein refers to a group having tworings joined by a spirocyclic linkage through a common single carbonatom, wherein each ring is a 4-7-membered ring (including the commoncarbon atom).

The term “heterospirocyclic” as used herein refers to a group having tworings joined by a spirocyclic linkage through a carbon atom, whereineach ring has 4 to 6 ring atoms (with one ring carbon atom being commonto both rings), and wherein one of the ring atoms is a nitrogen atom.

The term “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The term “tautomer” as used herein refers to compounds whose structuresdiffer markedly in arrangement of atoms, but which exist in easy andrapid equilibrium, and it is to be understood that compounds providedherein may be depicted as different tautomers, and when compounds havetautomeric forms, all tautomeric forms are intended to be within thescope of the invention, and the naming of the compounds does not excludeany tautomer.

It will be appreciated that certain compounds provided herein maycontain one or more centers of asymmetry and may therefore be preparedand isolated in a mixture of isomers such as a racemic mixture, or in anenantiomerically pure form.

In certain embodiments of Formula I, X¹, X², X³ and X⁴ are independentlyCH or CF. In certain embodiments, each of X¹, X², X³ and X⁴ is CH.

In certain embodiments of Formula I, X¹, X², X³ and X⁴ are independentlyCH, CF or N, wherein one of X¹, X², X³ and X⁴ is N and the remainder areindependently CH or CF. In certain embodiments of Formula I, X¹ is N,and X², X³ and X⁴ are independently CH or CF. In certain embodiments, X¹is N, and X², X³ and X⁴ are CH.

In certain embodiments of Formula I, X¹, X², X³ and X⁴ are independentlyCH, CF or N, wherein two of X¹, X², X³ and X⁴ are N. In certainembodiments of Formula I, X¹ and X³ are N and X² and X⁴ areindependently CH or CF. In one embodiment, X¹ and X³ are N and X² and X⁴are CH.

In certain embodiments of Formula I, A is H.

In certain embodiments of Formula I, A is Cl.

In certain embodiments of Formula I, A is CN.

In certain embodiments of Formula I, A is methyl.

In certain embodiments of Formula I, A is ethyl.

In certain embodiments of Formula I, A is cyclopropyl.

In certain embodiments of Formula I, B is hydrogen.

In certain embodiments of Formula I, B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros. Non-limiting examples include methyl,ethyl, propyl, isopropyl, isobutyl, sec-butyl, 2-ethylbutyl, neopentyl,difluoromethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. In certainembodiments, B is methyl or ethyl.

In certain embodiments of Formula I, B is hydroxyC2-C6 alkyl wherein thealkyl portion is optionally substituted with a C3-C6 cycloalkylidenering. In certain embodiments, the alkyl portion is unsubstituted.Non-limiting examples include the structures:

In certain embodiments of Formula I, B is dihydroxyC3-C6 alkyl- whereinthe alkyl portion is optionally substituted with a C3-C6 cycloalkylidenering. A non-limiting example includes 2,3-dihydroxypropyl.

In certain embodiments of Formula I, B is (C1-C6 alkoxy)C1-C6 alkyl-optionally substituted with 1-3 fluoros. In certain embodiments ofFormula I, B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with1-3 fluoros. Non-limiting examples include the structures:

In certain embodiments of Formula I, B is (R¹R²N)C1-C6 alkyl-, where R¹and R² are independently H, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6alkoxy)C(═O)—. Non-limiting examples of (R¹R²N)C1-C6 alkyl- include thestructures:

In certain embodiments of Formula I, B is hetAr¹C1-C3 alkyl-, wherehetAr¹ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and is optionally substitutedwith one or more independently selected C1-C6 alkyl substituents. Incertain embodiments, hetAr¹ is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N and O and is optionallysubstituted with C1-C6 alkyl. Non-limiting examples of hetAr¹C1-C3alkyl- include the structures:

In certain embodiments of Formula I, B is (C3-C6 cycloalkyl)C1-C3 alkyl-wherein said cycloalkyl is optionally substituted with OH. Anon-limiting example is cyclobutylmethyl.

In certain embodiments of Formula I, B is (hetCyc^(a))C1-C3 alkyl-,where hetCyc^(a) is as defined for Formula I. In certain embodiments ofFormula I, B is (hetCyc^(a))C1-C3 alkyl-, where hetCyc^(a) is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O and is optionally substituted with one or moresubstituents independently selected from OH, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, halogen, (C1-C6alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(═O)—. Non-limitingexamples include the structures:

In certain embodiments of Formula I, B is hetCyc^(a), where hetCyc² isas defined for Formula I. In certain embodiments, hetCyc^(a) is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O and is optionally substituted with OH, C1-C6 alkyl(optionally substituted with 1-3 fluoros) or hydroxyC1-C6 alkyl-.Non-limiting examples include the structures:

In certain embodiments of Formula I, B is (R¹R²N)C(═O)C1-C6 alkyl- whereR¹ and R² are independently selected from H and C1-C6 alkyl.Non-limiting examples include the structures:

In certain embodiments of Formula I, B is (R¹R²N)C(═O)—, where R¹ and R²are independently selected from H and C1-C6 alkyl. Non-limiting examplesinclude the structure:

In certain embodiments of Formula I, B is hetCyc^(a)C(═O)C1-C6 alkyl-where hetCyc^(a) is as defined for Formula I. A non-limiting exampleincludes the structure:

In certain embodiments of Formula I, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl- wherein thealkyl portion is optionally substituted with a C3-C6 cycloalkylidenering. In certain embodiments of Formula I, B is (b) C1-C6 alkyloptionally substituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl-.

Referring now to Ring D of Formula I,

Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen, (ii) a saturated 7-8membered bridged heterocyclic ring having one ring heteroatom which isnitrogen, or (iii) a saturated 7-11 membered heterospirocyclic ringsystem having one ring heteroatom which is nitrogen, wherein the E groupmay be bonded to any ring carbon atom of Ring D, each R^(a) may bebonded to any ring carbon atom of Ring D, and R^(b) may be bonded to anyring carbon of Ring D, provided that the ring carbon atom bonded to theE group is optionally substituted with only one of R^(a) or R^(b).

In one embodiment, Ring D is a saturated monocyclic 4-7 memberedheterocyclic ring having one ring heteroatom which is nitrogen. Thephrase “having one ring heteroatom which is nitrogen” when Ring D is asaturated monocyclic 4-7 membered heterocyclic ring means that said ringnitrogen atom is the nitrogen atom shown in Ring D of Formula I.Nonlimiting examples include the structures:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I. In one embodiment, n is 0, 1, 2, 3 or 4. In oneembodiment, n is 0, 1 or 2. In one embodiment, n is 0. In oneembodiment, n is 1. In one embodiment, n is 2. In one embodiment, m is 0or 1. In one embodiment, m is 0. In one embodiment, m is 1. In oneembodiment, n is 0 and m is 0 or 1. In one embodiment, n is 0 or 1 and mis 0.

In one embodiment of Formula I, Ring D is a saturated monocyclic 4-6membered heterocyclic ring having one ring heteroatom which is nitrogenselected from the structures

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I. In one embodiment, n is 0, 1, 2, 3 or 4. In oneembodiment, n is 0, 1 or 2. In one embodiment, n is zero. In oneembodiment, n is one. In one embodiment, n is two. In one embodiment, mis 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1.

In certain embodiments of Formula I, Ring D is a saturated monocyclic5-6 membered heterocyclic ring having one ring heteroatom which isnitrogen having the structure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I. In one embodiment, each R^(a) is independentlyselected from C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-. In one embodiment, nis 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, nis 1. In one embodiment, n is 2. In one embodiment, R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂— (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—, (k) hetCyc^(b)C(═O)NH— or (l)hetAr^(a)C(═O)NH—; R^(c) is hydrogen or C1-C6 alkyl; hetCyc^(b) is asdefined for Formula I; R^(d) is hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl(optionally substituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—,(C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl. In one embodiment, m is 0 or 1.In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment,Ring D is a saturated monocyclic 6 membered heterocyclic ring having onering heteroatom which is nitrogen. In one embodiment, Ring D is asaturated monocyclic 5 membered heterocyclic ring having one ringheteroatom which is nitrogen

In certain embodiments of Formula I, Ring D is a saturated monocyclic4-6 membered heterocyclic ring having one ring heteroatom which isnitrogen selected from the structures:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I. In one embodiment, each R^(a) is independentlyselected from C1-C6 alkyl (optionally substituted with 1-3 fluoros) or(C1-C6 alkoxy)C1-C6 alkyl-. In one embodiment, n is 0, 1, 2, 3 or 4. Inone embodiment, n is 0, 1 or 2. In one embodiment, n is 0. In oneembodiment, n is one. In one embodiment, R^(b) is (a) hydroxy, (c)hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) areindependently H or C1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—,(g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portionis optionally substituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- orR′R″N—, or said alkyl portion is optionally substituted with twosubstituents independently selected from R′R″N— and OH, where each R′and R″ is independently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ are independentlyhydrogen or C1-C6 alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—, (k)hetCyc^(b)C(═O)NH— or (l) hetAr^(a)C(═O)NH—; hetCyc^(b) is as definedfor Formula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen,C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) andR^(l) are independently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl-where R^(m) and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl. In one embodiment, m is 0 or 1.In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment,n is 0 or 1 and m is 0 or 1. Non-limiting examples when Ring D is anoptionally substituted saturated 4-7 membered heterocyclic ring includethe structures:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, and asterisk indicates the point ofattachment to the E group.

In one embodiment, Ring D is a saturated monocyclic 6 memberedheterocyclic ring having one ring heteroatom which is nitrogen which maybe represented by the structure:

where n and m are zero, that is, Ring D may be represented by thestructure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, and the asterisk indicates the pointof attachment to the E group.

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; E is (a) hydrogen, (b)hydroxy, (c) C1-C6 alkyl optionally substituted with 1-3 fluoros, (d)Ar¹C1-C6 alkyl wherein said alkyl portion is optionally substituted with1-3 fluoros, (e) hetAr²C1-C6 alkyl, (f) (C1-C6 alkoxy)C1-C6 alkoxy-, (g)Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (j)hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, (m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1, (n)R⁴R⁵NC(═O)—, (o) Ar¹NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl, (p)hetAr²NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl, (r) hetCyc⁵C(═O)—,(s) R⁴R⁵NC(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, (t) C1-C6alkyl)SO₂—, (u) Ar¹(C1-C6 alkyl)C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, (v) hetAr⁴C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, (w)hetAr²—S(═O)—, (x) (C3-C6 cycloalkyl)CH₂SO₂—, (y) Ar¹(C1-C6 alkyl)SO₂—,(z) hetAr²SO₂—, (aa) Ar¹, (bb) hetAr², (cc) hetCyc⁵, (dd) C1-C6 alkoxy,(ee) Ar¹(C1-C6 alkyl)-O—, (ff) hetAr²(C1-C6 alkyl)-O—, (gg)hetAr²—O—C1-C6 alkyl-, (hh) Ar¹(C1-C6 alkyl)NR^(g)— where R^(g) is H orC1-C6 alkyl, (ii) hetAr²—S—, (jj) Ar²SO₂NR(CH₂)_(p)— where p is 0 or 1and R^(g) is H or C1-C6 alkyl, (kk) (C1-C6 alkoxy)C(═O)—, (11) (C1-C6alkyl)NR^(g)C(═O)O— where R^(g) is H or C1-C6 alkyl, (mm) (C1-C6alkyl)NR^(g)SO₂— where R^(g) is H or C1-C6 alkyl, (nn)hetCyc⁵C(═O)NR^(g)—, (oo) Q-NR^(h)(C1-C3 alkyl)C(═O)NR^(g)— where R^(g)and R^(h) are independently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or(C1-C6 alkyl)OC(═O)—,

where R^(g) and R^(h) are independently H or C1-C6 alkyl, Q is H, C1-C6alkyl or (C1-C6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,

where R^(g) and R^(h) are independently H or C1-C6 alkyl and Q is H,C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,

where R^(g) is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—, (ss) R^(g)R^(h)N— where R^(g) and R^(h) are independentlyH or C1-C6 alkyl, (tt) (C3-C6 cycloalkyl)C(═O)NR^(g)— where thecycloalkyl is optionally and independently substituted with one or morehalogens, (uu) (C1-C6 alkyl)C(═O)NR^(g)CH₂— where R^(g) is H or C1-C6alkyls, or (vv) C1-C6 alkyl)SO₂NR^(g)— where R^(g) is H or C1-C6 alkyl;each R^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—, (k) hetCyc^(b)C(═O)NH— or (l)hetAr^(a)C(═O)NH—; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen,C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—,(R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) are independently H orC1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) areindependently H or C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, orhetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclic ring having aring heteroatom selected from N and O and optionally substituted withC1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and Ar¹, hetAr²,hetAr^(a), hetCyc^(b), hetCyc⁵, R^(g), R³, R⁴, and R⁵ are as defined forFormula I. In one embodiment, each R^(a) is independently selected froma C1-C6 substituent (optionally substituted with 1-3 fluoros). In oneembodiment, R^(b) is (a) hydroxy, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (h) (C1-C4alkyl)-C(═O)NH— wherein said alkyl portion is optionally substitutedwith hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkylportion is optionally substituted with two substituents independentlyselected from R′R″N— and OH, where each R′ and R″ is independentlyhydrogen or C1-C6 alkyl, or (k) hetCyc^(b)C(═O)NH—; R^(c) is hydrogen orC1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substituted with1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; hetCyc^(b) and hetAr^(a) are asdefined for Formula I, n is 0, 1 or 2; and m is 0 or 1. In oneembodiment, R^(b) is (a) OH, (c) hetCyc^(b)CH₂— wherein hetCyc^(b) is a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein hetCyc^(b) is optionally substituted withC1-C6 alkyl (optionally substituted with 1-3 fluoros), (e) R^(c)R^(d)N—or (f) R^(c)R^(d)NCH₂—; R^(c) is hydrogen or C1-C6 alkyl; and R^(d) ishydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros).

In one embodiment, Ring D is a saturated monocyclic 6-memberedheterocyclic ring having one ring heteroatom which is nitrogen which maybe represented by the structure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, and the asterisk indicates the pointof attachment to the E group, and R^(a) is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6alkyl-. In one embodiment, R^(a) is C1-C6 alkyl.

In one embodiment, Ring D is a saturated monocyclic 6-memberedheterocyclic ring having one ring heteroatom which is nitrogen which maybe represented by the structures:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, and the asterisk indicates the pointof attachment to the E group, and R^(b) is (a) hydroxy, (b) cyclopropyl,(c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j)are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—, (f)R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH— whereinsaid alkyl portion is optionally substituted with hetCyc^(b), hetAr^(a),C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionally substitutedwith two substituents independently selected from R′R″N— and OH, whereeach R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—,(k) hetCyc^(b)C(═O)NH— or (l) hetAr^(a)C(═O)NH—; R^(c) is hydrogen orC1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substituted with1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl. In one embodiment, R^(b) is (a)OH, (c) hetCyc^(b)CH₂—, (e) R^(c)R^(d)N— or (f) R^(c)R^(d)NCH₂—; R^(c)is hydrogen or C1-C6 alkyl; R^(d) is hydrogen or C1-C6 alkyl (optionallysubstituted with 1-3 fluoros); and hetCyc^(b) is as defined for FormulaI. In one embodiment, R^(b) is (c) hetCyc^(b)CH₂—, (e) R^(c)R^(d)N— or(f) R^(c)R^(d)NCH₂—; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogenor C1-C6 alkyl (optionally substituted with 1-3 fluoros); and hetCyc^(b)is as defined for Formula I.

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; E is (d) Ar¹C1-C6 alkyl-wherein said alkyl portion is optionally substituted with 1-3 fluoros,(e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (k) R³C(═O)NR^(g) whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, (m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1, or (n)R⁴R⁵NC(═O)— where n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and Ar¹,hetAr², R^(g), R³, R⁴, and R⁵ are as defined for Formula I. In oneembodiment, each R^(a) is independently selected from a C1-C6substituent, R^(b) is OH or R^(c)R^(d)N— where R^(c) is hydrogen orC1-C6 alkyl and R^(d) is hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(═O)—;n is 0, 1 or 2; and m is 0 or 1.

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; E is hydrogen; each R^(a)is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂— where hetCyc^(b) is a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) areindependently H or C1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—,(g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portionis optionally substituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- orR′R″N—, or said alkyl portion is optionally substituted with twosubstituents independently selected from R′R″N— and OH, where each R′and R″ is independently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ are independentlyhydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b)is as defined for Formula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) ishydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—,(R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) are independently H orC1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) areindependently H or C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, orhetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclic ring having aring heteroatom selected from N and O and optionally substituted withC1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; and m is 0 or 1. In oneembodiment, Ring D is a saturated 6 membered heterocyclic ring havingone ring heteroatom. In one embodiment, Ring D is a saturated 5 memberedheterocyclic ring having one ring heteroatom. In one embodiment, R^(b)is OH or R^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyl and R^(d)is hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)C(═O)— or PhCH₂—. In oneembodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0and m is 0 or 1. Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hydroxy. In one embodiment, n is 0, 1 or 2 and m is0 or 1. In one embodiment, Ring D is a saturated 6 membered heterocyclicring having one ring heteroatom which is nitrogen. In one embodiment,R^(b) is R^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyl and R^(d)is hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(═O)—. In one embodiment, nis 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1.A non-limiting example includes the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is C1-C6 alkyl optionally substituted with 1-3 fluoros.In one embodiment, Ring D is a saturated 6 membered heterocyclic ringhaving one ring heteroatom which is nitrogen. In one embodiment, R^(b)is OH or R^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyl and R^(d)is hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(═O)—. In one embodiment, nis 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1.Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen, R^(a), R^(b), n, and m areas defined for Formula I, and E is Ar¹C1-C6 alkyl wherein said alkylportion is optionally substituted with 1-3 fluoros and where Ar¹ is asdefined for Formula I. In one embodiment, Ring D is a saturated 4-7membered heterocyclic ring having one ring heteroatom which is nitrogen;each R^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂— or (k) hetCyc^(b)C(═O)NH—;hetCyc^(b) is as defined for Formula I; R^(c) is hydrogen or C1-C6alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹C1-C6 alkyl, wherein said alkyl portion isoptionally substituted with 1-3 fluoros and where Ar¹ is as defined forFormula I. In one embodiment, Ring D is a saturated 6 memberedheterocyclic ring having one ring heteroatom which is nitrogen. In oneembodiment, R^(b) is OH. In one embodiment, n is 0, 1 or 2 and m is 0or 1. In one embodiment, n is 0 and m is 0 or 1. Non-limiting examplesinclude the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—,(k) hetCyc^(b)C(═O)NH— or (l) hetAr^(a)C(═O)NH—; hetAr^(a) andhetCyc^(b) are as defined for Formula I; R^(c) is hydrogen or C1-C6alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²C1-C6 alkyl, where hetAr¹ is as defined forFormula I. In one embodiment, hetAr² is a 5-6 membered heteroaryl ringhaving 1-2 ring nitrogen atoms and optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), andC1-C6 alkoxy (optionally substituted with 1-3 fluoros). In oneembodiment, Ring D is a saturated 6 membered heterocyclic ring havingone ring heteroatom which is nitrogen. In one embodiment, n is 0 or 1and m is 0 or 1. In one embodiment, n is 0 and m is 0. In oneembodiment, n is 0 and m is 1. In one embodiment, R^(b) is (a) hydroxy,(e) R^(c)R^(d)N—, (h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portionis optionally substituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- orR′R″N—, or said alkyl portion is optionally substituted with twosubstituents independently selected from R′R″N— and OH, where each R′and R″ is independently hydrogen or C1-C6 alkyl, (k) hetCyc^(b)C(═O)NH—or (l) hetAr^(a)C(═O)NH—. Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C1-C6 alkoxy)C1-C6 alkoxy-. In one embodiment, n is0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In oneembodiment, n is 0 and m is 1. In one embodiment, R^(b) is R^(c)R^(d)N—.Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹O—, where Ar¹ is as defined for Formula I. In oneembodiment, Ar¹ is unsubstituted or substituted with one or moresubstituents independently selected from halogen, CN and C1-C6 alkyl(optionally substituted with 1-3 fluoros). In one embodiment, Ring D isa saturated 4 or 6 membered heterocyclic ring having one ring heteroatomwhich is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. Inone embodiment, n is 0 and m is 0. Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²O—, where hetAr² is as defined for Formula I.In one embodiment, hetAr² is a 5-6-membered heteroaryl ring having 1-2ring heteroatoms independently selected from N and O and is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C1-C6 alkoxy (optionally substitutedwith 1-3 fluoros), C1-C6 alkyl (optionally substituted with 1-3 fluoros)and hydroxyC1-C6 alkoxy. In one embodiment, Ring D is a saturated 4-6membered heterocyclic ring having one ring heteroatom which is nitrogen.In one embodiment, Ring D is a saturated 5-6 membered heterocyclic ringhaving one ring heteroatom which is nitrogen. In one embodiment, n is 0or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In oneembodiment, n is 0 and m is 1. In one embodiment, R^(a) is C1-C6 alkyl.In one embodiment, R^(b) is R^(c)R^(d)N—. Non-limiting examples includethe structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹NR^(g)—, where Ar¹ is as defined for Formula Iand R^(g) is H or C1-C6 alkyl. In one embodiment, Ar¹ is optionallysubstituted with one or more halogens. In one embodiment, Ring D is asaturated 6 membered heterocyclic ring having one ring heteroatom whichis nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In oneembodiment, n is 0 and m is 0. A non-limiting example includes thestructure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²NR^(g)— where hetAr² is a defined for FormulaI and R^(g) is H or C1-C6 alkyl. In one embodiment, hetAr² is a pyridylring optionally substituted with one or more substituents independentlyselected from C1-C6 alkyl and halogen. In one embodiment, n is 0, 1 or 2and m is 0 or 1. In one embodiment, R^(a) is C1-C6 alkyl. In oneembodiment, n is 0 and m is 0. Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is R³C(═O)NR^(g)— where R³ and R^(g) are as defined forFormula I. In one embodiment, R^(g) is hydrogen. In one embodiment, RingD is a saturated 6 membered heterocyclic ring having one ring heteroatomwhich is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. Inone embodiment, n is 0 or 1 and m is 0. In one embodiment, m is 1 and nis 0. In one embodiment, R^(a) is C1-C6 alkyl (optionally substitutedwith 1-3 fluoros). In one embodiment, R^(b) is hydroxy, hetCyc^(b)CH₂—,R^(c)R^(d)N—, R^(c)R^(d)NCH₂—, C1-C6 alkoxy, (R′R″N)C1-C6alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ are independentlyhydrogen or C1-C6 alkyl, or hetCyc^(b)(C1-C3 alkyl)OCH₂—, wherehetCyc^(b), R^(c) and R^(d) are as defined for Formula I. In oneembodiment, R^(b) is hetCyc^(b)CH₂— where hetCyc^(b) is a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein hetCyc^(b) is optionally substituted with one ormore substituents independently selected from OH, C1-C6 alkyl(optionally substituted with 1-3 fluoros), and R′R″N— where R′ and R″are independently hydrogen or C1-C6 alkyl. In one embodiment, R^(b) isR^(c)R^(d)N— or R^(c)R^(d)NCH₂— where R^(c) is hydrogen or C1-C6 alkyland R^(d) is hydrogen or C1-C6 alkyl (optionally substituted with 1-3fluoros). Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹C(═O)NR^(g)— where Ar¹ is as defined for FormulaI. In one embodiment, Ar¹ is unsubstituted or substituted with one ormore substituents independently selected from halogen, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyC1-C6 alkyl,(C1-C6 alkyl)SO₂—, and (R^(e)R^(f)N)C1-C6 alkyl- where each R^(e) andR^(f) is independently H or C1-C6 alkyl. In one embodiment, Ring D is asaturated 5-6 membered heterocyclic ring having one ring heteroatomwhich is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. Inone embodiment, n is 0 or 1 and m is 0. In one embodiment, n is 1 and mis 0. In one embodiment, n is 0 and m is 1. In one embodiment, R^(a) isC1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyC1-C6alkyl. In one embodiment, R^(b) is C1-C6 alkoxy, hetCyc^(b)CH₂— orR^(c)R^(d)NCH₂—, where hetCyc^(b), R and R^(d) are as defined forFormula I. In one embodiment, R^(b) is hetCyc^(b)CH₂— where hetCyc^(b)is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc^(b) is optionallysubstituted with one or more substituents independently selected fromOH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros) and(C1-C6 alkoxy)C1-C6 alkyl-. In one embodiment, R^(b) is R^(c)R^(d)NCH₂—where R^(c) is H or C1-C6 alkyl and R^(d) is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros). In one embodiment, R^(b) is hydroxyl.Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1, andhetAr² and R^(g) are as defined for Formula I. In one embodiment, hetAr²is a 5-6-membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, C1-C6 alkyl (optionally substituted with 1-3fluoros) and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). Inone embodiment, Ring D is a saturated 6 membered heterocyclic ringhaving one ring heteroatom which is nitrogen. In one embodiment, n is 0,1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. Inone embodiment, R^(a) is C1-C6 alkyl (optionally substituted with 1-3fluoros) or hydroxyC1-C6 alkyl. In one embodiment, R^(b) is hydroxy,hetCyc^(b)CH₂—, R^(c)R^(d)NCH₂—, C1-C6 alkoxy, or hetCyc^(b)(C1-C3alkyl)OCH₂—, where hetCyc^(b), R^(c) and R^(d) are as defined forFormula I. In one embodiment, R^(b) is hetCyc^(b)CH₂— where hetCyc^(b)is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc^(b) is optionallysubstituted with one or more substituents independently selected fromC1-C6 alkyl (optionally substituted with 1-3 fluoros). In oneembodiment, R^(b) is R^(c)R^(d)NCH₂— where R^(c) is H or C1-C6 alkyl andR^(d) is C1-C6 alkyl (optionally substituted with 1-3 fluoros).Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is R⁴R⁵NC(═O)— where R⁴ and R⁵ are as defined forFormula I. In one embodiment, Ring D is a saturated 6 memberedheterocyclic ring having one ring heteroatom which is nitrogen. In oneembodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or1 and m is 0. In one embodiment, R^(a) is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros) or hydroxyC1-C6 alkyl. In one embodiment,R^(b) is hetCyc^(b)CH₂—, R^(c)R^(d)NCH₂—, or hetCyc^(b)(C1-C3alkyl)OCH₂—, where hetCyc^(b), R^(c) and R^(d) are as defined forFormula I. In one embodiment, R^(b) is hetCyc^(b)CH₂— where hetCyc^(b)is a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclicring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2ring heteroatoms independently selected from N and O, wherein hetCyc^(b)is optionally substituted with one or more substituents independentlyselected from fluoro, C1-C6 alkyl (optionally substituted with 1-3fluoros), C1-C6 alkoxy, (C1-C6 alkoxy)C(═O)—, and R′R″N— where R′ and R″are independently hydrogen or C1-C6 alkyl. In one embodiment, R^(b) isR^(c)R^(d)NCH₂— where R^(c) is H or C1-C6 alkyl and R^(d) is C1-C6 alkyl(optionally substituted with 1-3 fluoros). Non-limiting examplesincludes the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹NR^(g)C(═O)— where Ar¹ and R^(g) are as definedfor Formula I. In one embodiment, Ar¹ is unsubstituted or substitutedwith one or more halogens. In one embodiment, m is 0. In one embodimentn is 0 or 1. In one embodiment, R^(a) is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros). Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²NR^(g)C(═O)— where hetAr² and R^(g) are asdefined for Formula I. In one embodiment, hetAr¹ is a 5-6 memberedheteroaryl having 1-2 ring nitrogen atoms and optionally substitutedwith one or more substituents independently selected from C1-C6 alkyl(optionally substituted with 1-3 fluoros) and C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros). In one embodiment, m is 0. In oneembodiment n is 0 or 1. In one embodiment, R^(a) is C1-C6 alkyl(optionally substituted with 1-3 fluoros). Non-limiting examples includethe structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetCyc⁵C(═O)— where hetCyc⁵ is as defined forFormula I. In one embodiment, m is 0. In one embodiment n is 0 or 1. Inone embodiment, R^(a) is C1-C6 alkyl (optionally substituted with 1-3fluoros). A non-limiting example is the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is R⁴R⁵NC(═O)NR^(g)— where R⁴, R⁵ and R^(g) are asdefined for Formula I. In one embodiment, R⁴ and R⁵ are independentlyhydrogen or C1-C6 alkyl. In one embodiment, Ring D is a saturated 6membered heterocyclic ring having one ring heteroatom which is nitrogen.In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, nis 0 or 1 and m is 0. In one embodiment, R^(a) is C1-C6 alkyl(optionally substituted with 1-3 fluoros). In one embodiment, n is 0 andm is 1. In one embodiment, R^(b) is hetCyc^(b)CH₂— where hetCyc^(b) is a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein hetCyc^(b) is optionally substituted withC1-C6 alkyl (optionally substituted with 1-3 fluoros). In oneembodiment, R^(b) is R^(c)R^(d)NCH₂— where R^(c) is H or C1-C6 alkyl andR^(d) is C1-C6 alkyl (optionally substituted with 1-3 fluoros).Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C1-C6 alkyl)SO₂—. In one embodiment, Ring D is asaturated 6 membered heterocyclic ring having one ring heteroatom whichis nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In oneembodiment, n is 0 or 1 and m is 0. In one embodiment, R^(a) is C1-C6alkyl (optionally substituted with 1-3 fluoros). Non-limiting examplesinclude the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹(C1-C6 alkyl)C(═O)NR^(g)— where Ar¹ and R^(g) areas defined for Formula I. In one embodiment, Ar¹ is unsubstituted orsubstituted with one or more halogens. In one embodiment, n is 0 or 1and m is 0. In one embodiment, R^(a) is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros). Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr⁴C(═O)NR^(g)— where hetAr⁴ and R^(g) are asdefined for Formula I. In one embodiment, n is 0 or 1 and m is 0. In oneembodiment, R^(a) is C1-C6 alkyl. Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²—S(═O)— where hetAr² is as defined for FormulaI. In one embodiment, hetAr² is a 5-6-membered heteroaryl ring. In oneembodiment, hetAr² is unsubstituted. In one embodiment, n is 0. In oneembodiment, m is 0. A non-limiting example includes the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C3-C6 cycloalkyl)CH₂SO₂—. In one embodiment, n is0. In one embodiment, m is 0. A non-limiting example includes thestructure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹(C1-C6 alkyl)SO₂— where Ar¹ is as defined forFormula I. In one embodiment, Ar¹ is unsubstituted. In one embodiment, nis 0. In one embodiment, m is 0. A non-limiting example includes thestructure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²SO₂— where hetAr² is as defined for Formula I.In one embodiment, hetAr² is a 5-6-membered heteroaryl ring. In oneembodiment, hetAr² is unsubstituted. In one embodiment, n is 0. In oneembodiment, m is 0. A non-limiting example includes the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹ where Ar¹ is as defined for Formula I. In oneembodiment, Ar¹ is unsubstituted. In one embodiment, n is 0. In oneembodiment, m is 0 or 1. In one embodiment, R^(b) is OH. A non-limitingexample includes the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂— (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr² where hetAr² is as defined for Formula I. Inone embodiment, hetAr² is unsubstituted or substituted with C1-C6 alkyl(optionally substituted with 1-3 fluoros). In one embodiment, n is 0. Inone embodiment, m is 0 or 1. In one embodiment, R^(b) is OH.Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetCyc⁵ where hetCyc⁵ is as defined for Formula I.In one embodiment, m is 0. In one embodiment, n is 0 or 1. In oneembodiment, R^(a) is C1-C6 alkyl (optionally substituted with 1-3fluoros). Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is C1-C6 alkoxy. In one embodiment, n is 0. In oneembodiment, m is 0 or 1. In one embodiment, R^(b) is R^(c)R^(d)N— whereR^(c) is H and R^(d) is H. Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹(C1-C6 alkyl)-O— where Ar¹ is as defined forFormula I. In one embodiment, Ar¹ is unsubstituted. In one embodiment, nis 0. In one embodiment, m is 0. Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4alkyl)-C(═O)NH— wherein said alkyl portion is optionally substitutedwith hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkylportion is optionally substituted with two substituents independentlyselected from R′R″N— and OH, where each R′ and R″ is independentlyhydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0or 1 and R′ and R″ are independently hydrogen or C1-C6 alkyl, or (j)hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I;(d) R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently Hor C1-C6 alkyl, (e) R^(c)R^(d)N—, or (f) R^(c)R^(d)NCH₂—; R^(c) ishydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl(optionally substituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—,(C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²(C1-C6 alkyl)-O— where hetAr² is as definedfor Formula I. In one embodiment, hetAr² is a 5-6-membered heteroarylring. In one embodiment, hetAr² is unsubstituted. In one embodiment, nis 0. In one embodiment, m is 0. Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²—O—C1-C6 alkyl- where hetAr² is as defined forFormula I. In one embodiment, hetAr² is a 5-6-membered heteroaryl ring.In one embodiment, hetAr² is unsubstituted. In one embodiment, n is 0.In one embodiment, m is 0. Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar¹(C1-C6 alkyl)NR^(g)— where Ar¹ and R^(g) are asdefined for Formula I. In one embodiment, Ar¹ is unsubstituted orsubstituted with one or more halogens. In one embodiment, m is 0. In oneembodiment, n is 0 or 1. In one embodiment, R¹ is C1-C6 alkyl(optionally substituted with 1-3 fluoros). Non-limiting examples includethe structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetAr²—S— where hetAr² is as defined for Formula I.In one embodiment, hetAr² is a 5-6-membered heteroaryl ring. In oneembodiment, hetAr² is unsubstituted. In one embodiment, n is 0. In oneembodiment, m is 0. A non-limiting example is the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Ar²SO₂NR^(g)(CH₂)_(p)— where p is 0 or 1, R^(g) is Hor C1-C6 alkyl, and Ar² is as defined for Formula I. In one embodiment,p is 0. In one embodiment, p is 1. In one embodiment, Ar² is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), C3-C6 cycloalkyl, and R^(g)R^(h)N— whereR^(g) and R^(h) are independently H or C1-C6 alkyl. In one embodiment,Ar² is phenyl optionally substituted with one or more independentlyselected C1-C6 alkyl (optionally substituted with 1-3 fluoros)substituents. In one embodiment, m is 0 or 1. In one embodiment, n is 0.Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C1-C6 alkoxy)C(═O)—. In one embodiment, m is 0. Inone embodiment, n is 0 or 1. In one embodiment, R^(a) is hydroxyC1-C6alkyl. Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C1-C6 alkyl)NR^(g)C(═O)O— where R^(g) is H or C1-C6alkyl. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In oneembodiment, R^(a) is C1-C6 alkyl (optionally substituted with 1-3fluoros). Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C1-C6 alkyl)NR^(g)SO₂— where R^(g) is H or C1-C6alkyl. In one embodiment, m is 0. In one embodiment, n is 0. Anon-limiting example is the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hetCyc⁵C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyland hetCyc⁵ is as defined for Formula I. In one embodiment, hetCyc⁵ is a5-6 membered heterocyclic ring having a ring nitrogen atom. In oneembodiment, m is 0 or 1. In one embodiment, n is 0. In one embodiment,R^(b) is R^(c)R^(d)NCH₂— where R and R^(d) are as defined for Formula I.In one embodiment, R^(c) and R^(d) are hydrogen or C1-C6 alkyl.Non-liming examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is Q-NR^(h)(C1-C3 alkyl)C(═O)NR^(g)— where R^(g) andR^(h) are independently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or(C1-C6 alkyl)OC(═O)—. In one embodiment, m is 0. In one embodiment, n is0 or 1. In one embodiment, R^(a) is C1-C6 alkyl (optionally substitutedwith 1-3 fluoros). Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is

where R^(g) and R^(h) are independently H or C1-C6 alkyl, Q is H, C1-C6alkyl or (C1-C6 alkyl)OC(═O)— and r is 1, 2, 3 or 4. In one embodiment,m is 0. In one embodiment, n is 0 or 1. In one embodiment, R^(a) isC1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limitingexamples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is

where R^(g) and R^(h) are independently H or C1-C6 alkyl and Q is H,C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—. In one embodiment, m is 0. In oneembodiment, n is 0 or 1. In one embodiment, R^(a) is C1-C6 alkyl(optionally substituted with 1-3 fluoros). Non-limiting examples includethe structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is

where R^(g) is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—. In one embodiment, m is 0. In one embodiment, n is 0or 1. In one embodiment, R^(a) is C1-C6 alkyl (optionally substitutedwith 1-3 fluoros). Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is R^(g)R^(h)N— where R^(g) and R^(h) are independentlyH or C1-C6 alkyl. In one embodiment, n is 0 or 1. In one embodiment, mis 0 or 1. In one embodiment, R^(b) is hydroxy, C1-C6 alkoxy- orhetCyc^(b)(C1-C3 alkyl)OCH₂—, where hetCyc^(b) is as defined for FormulaI. In one embodiment, hetCyc^(b) is a 5-6 membered heteroaryl ringhaving 1-2 ring heteroatoms independently selected from N and O.Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C3-C6 cycloalkyl)C(═O)NR^(g)— where the cycloalkylis optionally and independently substituted with one or more halogens. Anon-limiting example includes the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is (C1-C6 alkyl)C(═O)NR^(g)CH₂— where R^(g) is H orC1-C6 alkyl. A non-limiting example includes the structure:

In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is C1-C6 alkyl)SO₂NR^(g)— where R^(g) is H or C1-C6alkyl. A non-limiting example includes the structure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen. Thephrase “having one ring heteroatom which is nitrogen” when Ring D is asaturated 7-8 membered bridged heterocyclic ring means that the one ringnitrogen atom is the nitrogen atom shown in Ring D of Formula I.Non-limiting examples include rings such as

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I. In one embodiment, n is 0 or 1. In oneembodiment, n is 0. In one embodiment, n is 1. In one embodiment, m is 0or 1. In one embodiment, m is 0. In one embodiment, m is 1. In oneembodiment, n is 0 and m is 0 or 1.

In one embodiment, Ring D is a saturated 7 membered bridged heterocyclicring having one ring heteroatom which is nitrogen. Non-limiting examplesinclude structures:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I. In one embodiment, n is 0 or 1 and m is 0 or 1.In one embodiment, n is 0 and m is 0 or 1. In one embodiment, R^(b) isR^(c)R^(d)N— where R^(c) is H or C1-C6 alkyl and R^(d) is H or C1-C6alkyl. In one embodiment, R^(b) is R^(c)R^(d)N— where R^(c) and R^(d)are H.

In one embodiment, Ring D is a saturated 7 membered bridged heterocyclicring having one ring heteroatom which is nitrogen having the structure

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(b) and m are as defined forFormula I. In one embodiment, m is 0. In one embodiment, m is 1. In oneembodiment, R^(b) is R^(c)R^(d)N— where R^(c) is H or C1-C6 alkyl andR^(d) is H or C1-C6 alkyl. In one embodiment, R^(b) is R^(c)R^(d)N—where R^(c) and R^(d) are H. Non-limiting examples include thestructures:

where the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment to the E group.

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen, and E isselected from (a) hydrogen, (b) hydroxy, (f) (C1-C6 alkoxy)C1-C6 alkoxy,(h) hetAr²O—, (j) hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl, (n)R⁴R⁵NC(═O)—, (o) Ar¹NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl, and(p) hetAr²NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl, where Ar¹,hetAr², R⁴ and R⁵ are as defined for Formula I.

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen, eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1 2, 3, 4, 5 or 6; m is 0 or 1; and E is hydrogen. In one embodiment,Ring D is a saturated 7 membered bridged heterocyclic ring having onering heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 andm is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. In oneembodiment, R^(b) is R^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyland R^(d) is hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(═O)—. Anon-limiting example includes the structure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hydroxy. In one embodiment,Ring D is a saturated 7 membered bridged heterocyclic ring having onering heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 andm is 0 or 1. In one embodiment, n is 0 and m is 0. A non-limitingexample includes the structure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkoxy)C1-C6 alkoxy.In one embodiment, Ring D is a saturated 7 membered bridged heterocyclicring having one ring heteroatom which is nitrogen. In one embodiment, nis 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. Anon-limiting example includes the structure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr²O— where hetAr² is asdefined for Formula I. In one embodiment hetAr² is a 5-6 memberedheteroaryl ring having 1-2 ring nitrogen atoms optionally substitutedwith one or more substituents independently selected from C1-C6 alkoxyand halogen. In one embodiment, hetAr² is unsubstituted. In oneembodiment, Ring D is a saturated 7 membered bridged heterocyclic ringhaving one ring heteroatom which is nitrogen. In one embodiment, n is 0,1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. Inone embodiment, n is 0 and m is 0. Non-limiting examples include thestructures:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr²NH— where hetAr² isas defined for Formula I. In one embodiment hetAr² is a 5-6 memberedheteroaryl ring having 1-2 ring nitrogen atoms and optionallysubstituted with one or more substituents independently selected fromC1-C6 alkoxy, halogen and C1-C6 alkoxy (optionally substituted with 1-3fluoros). In one embodiment, Ring D is a saturated 7 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen. In oneembodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0and m is 0. Non-limiting examples include the structures:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R³C(═O)NR^(g)— where R³ andR^(g) are as defined for Formula I. In one embodiment, n is 0 and m is0. A non-limiting example includes the structure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar¹C(═O)NH— where Ar¹ is asdefined for Formula I. In one embodiment, Ar¹ is unsubstituted. In oneembodiment, n is 0 and m is 0. A non-limiting example includes thestructure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr²C(═O)NR′— wherehetAr² and R′ are as defined for Formula I. In one embodiment, hetAr² isunsubstituted. In one embodiment, n is 0 and m is 0. A non-limitingexample includes the structure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R⁴R⁵NC(═O)— where R⁴ and R⁵are as defined for Formula I. In one embodiment, Ring D is a saturated 7membered bridged heterocyclic ring having one ring heteroatom which isnitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In oneembodiment, n is 0 and m is 0. Non-limiting examples includes thestructures:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar¹NR^(g)C(═O)—, where Ar¹and R^(g) areas defined for Formula I. In one embodiment, Ar¹ issubstituted with one or more substituents independently selected fromhalogen, CN and C1-C6 alkyl (optionally substituted with 1-3 fluoros).In one embodiment, Ar¹ is unsubstituted. In one embodiment, Ring D is asaturated 7 membered bridged heterocyclic ring having one ringheteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is0 or 1. In one embodiment, n is 0 and m is 0. A non-limiting exampleincludes the structure:

In one embodiment, Ring D is a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen; eachR^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a)hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; hetCyc^(b) is as defined forFormula I; R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr²NR^(g)C(═O)— wherehetAr² and R^(g) are as defined for Formula I. In one embodiment hetAr²is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms andoptionally substituted with one or more substituents independentlyselected from halogen and C1-C6 alkoxy. In one embodiment, Ring D is asaturated 7 membered bridged heterocyclic ring having one ringheteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is0 or 1. In one embodiment, n is 0 and m is 0. A non-limiting exampleincludes the structure:

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclicring system having one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1. The phrase “having one ring heteroatom which is nitrogen”when Ring D is a saturated 7-11 membered heterospirocyclic ring systemmeans that said one ring nitrogen is the ring nitrogen atom shown inRing D of Formula I. In one embodiment, Ring D is a saturated 9 memberedheterospirocyclic ring system having one ring heteroatom which isnitrogen. In one embodiment, Ring D is a 7-azaspiro[3.5]nonanyl ring,e.g., a 7-azaspiro[3.5]nonan-2-yl ring. Nonlimiting examples include thestructures:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I. In one embodiment, n is 0, 1 or 2 and m is 0or 1. In one embodiment, n is 0 or 1. In one embodiment, n is 0. In oneembodiment, n is 1. In one embodiment, m is 0 or 1. In one embodiment, mis 0. In one embodiment, m is 1. In one embodiment, n is 0 and m is 0.

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclicring system having one ring heteroatom which is nitrogen; each R^(a) isindependently C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy,(b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— whereR^(i) and R^(j) are independently H or C1-C6 alkyl, (e) R^(c)R^(d)N—,(f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH—wherein said alkyl portion is optionally substituted with hetCyc^(b),hetAr^(a), C1-C6 alkoxy- or R′R″N—, or said alkyl portion is optionallysubstituted with two substituents independently selected from R′R″N— andOH, where each R′ and R″ is independently hydrogen or C1-C6 alkyl, (i)(R′R″N)C1-C6 alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ areindependently hydrogen or C1-C6 alkyl, or (j) hetCyc^(b)(C1-C3alkyl)OCH₂—; hetCyc^(b) is as defined for Formula I; R^(c) is hydrogenor C1-C6 alkyl; R^(d) is hydrogen, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; mis 0 or 1; and E is hydrogen. In one embodiment, Ring D is a7-azaspiro[3.5]nonanyl ring, e.g., a 7-azaspiro[3.5]nonan-2-yl ring. Inone embodiment, n is 0 and m is 0 or 1. In one embodiment, R^(b) isR^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyl and R^(d) ishydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(═O)—. Non-limiting examplesinclude the structures:

In one embodiment, Formula I includes compounds of Formula I-A, wherein:

X¹, X², X³ and X⁴ are independently CH, CF or N, wherein zero, one ortwo of X¹, X², X³ and X⁴ is N;

A is H, CN, Cl, methyl, ethyl or cyclopropyl;

B is

(a) hydrogen,

(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,

(f) (R¹R²N)C1-C6 alkyl- where R¹ and R² are independently selected fromH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6 alkoxy)C(═O)—;

(g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andis optionally substituted with one or more independently selected C1-C6alkyl groups;

(h) (C3-C6 cycloalkyl)C1-C3 alkyl-,

(i) (hetCyc^(a))C1-C3 alkyl-,

(j) hetCyc^(a),

(k) (R¹R²N)C(═O)C1-C6 alkyl- where R¹ and R² are independently selectedfrom H and C1-C6 alkyl,

(l) (R¹R²N)C(═O)—, where R¹ and R² are independently selected from H andC1-C6 alkyl, or

(m) hetCyc^(a)C(═O)C1-C6 alkyl-;

hetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6alkoxy)C(═O)—;

Ring D is a saturated 4-7 membered heterocyclic ring having one ringheteroatom which is nitrogen;

each R^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-;

R^(b) is (a) hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—, (k) hetCyc^(b)C(═O)NH— or (1)hetAr^(a)C(═O)NH—;

hetCyc^(b) is a 4-6 membered heterocyclic ring, a 7-8 membered bridgedheterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinhetCyc^(b) is optionally substituted with one or more substituentsindependently selected from OH, fluoro, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6alkoxy)C(═O)—, C1-C6 alkoxy, and R′R″N— where R′ and R″ areindependently hydrogen or C1-C6 alkyl;

hetAr^(a) is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S herein hetAr^(a) is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3fluoros);

R^(c) is hydrogen or C1-C6 alkyl;

R^(d) is hydrogen, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl;

n is 0, 1, 2, 3, 4, 5 or 6;

m is 0 or 1;

E is

(a) hydrogen,

(b) hydroxy,

(c) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(d) Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros,

(e) hetAr²C1-C6 alkyl-,

(f) (C1-C6 alkoxy)C1-C6 alkoxy-,

(g) Ar¹O—,

(h) hetAr²O—,

(i) Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl,

(j) hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl,

(k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H orC1-C6 alkyl,

(n) R⁴R⁵NC(═O)—,

(o) Ar¹NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl,

(p) hetAr²NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl,

(r) hetCyc⁵C(═O)—,

(s) R⁴R⁵NC(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(t) (C1-C6 alkyl)SO₂—;

(u) Ar¹(C1-C6 alkyl)C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(v) hetAr⁴C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(w) hetAr²—S(═O)—,

(x) (C3-C6 cycloalkyl)CH₂SO₂—,

(y) Ar¹(C1-C6 alkyl)SO₂—,

(z) hetAr²SO₂—,

(aa) Ar¹,

(bb) hetAr²,

(cc) hetCyc⁵,

(dd) C1-C6 alkoxy,

(ee) Ar¹(C1-C6 alkyl)-O—,

(ff) hetAr²(C1-C6 alkyl)-O—,

(gg) hetAr²—O—C1-C6 alkyl-,

(hh) Ar¹(C1-C6 alkyl)NR^(g)— where R^(g) is H or C1-C6 alkyl, or

(ii) hetAr²—S—,

(jj) Ar²SO₂NR(CH₂)_(p)— where p is 0 or 1 and R^(g) is H or C1-C6 alkyl,

(kk) (C1-C6 alkoxy)C(═O)—,

(ll) (C1-C6 alkyl)NR^(g)C(═O)O— where R^(g) is H or C1-C6 alkyl,

(mm) (C1-C6 alkyl)NR^(g)SO₂— where R^(g) is H or C1-C6 alkyl,

(nn) hetCyc⁵C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(oo) Q-NR^(h)(C1-C3 alkyl)C(═O)NR^(g)— where R^(g) and R^(h) areindependently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—,

where R^(g) and R^(h) are independently H or C1-C6 alkyl, Q is H, C1-C6alkyl or (C1-C6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,

where R^(g) and R^(h) are independently H or C1-C6 alkyl and Q is H,C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,

where R^(g) is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—, or

(ss) R^(g)R^(h)N— where R^(g) and R^(h) are independently H or C1-C6alkyl,

(tt) (C3-C6 cycloalkyl)C(═O)NR^(g)— where the cycloalkyl is optionallyand independently substituted with one or more halogens,

(uu) (C1-C6 alkyl)C(═O)NR^(g)CH₂— where R^(g) is H or C1-C6 alkyl, or

(vv) C1-C6 alkyl)SO₂NR^(g)— where R^(g) is H or C1-C6 alkyl;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl,hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO₂—, R^(e)R^(f)N— and(R^(e)R^(f)N)C1-C6 alkyl- where each R^(e) and R^(f) is independently Hor C1-C6 alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S, or a 9-10 membered bicyclicheteroaryl having 1-2 ring nitrogen atoms, wherein hetAr² is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros) and hydroxyC1-C6 alkoxy-;

hetCyc⁵ is a 4-6 membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N, O and S wherein saidheterocyclic ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkoxy and oxo;

R³ is C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6cycloalkyl)CH₂—, (C3-C6 cycloalkyl)O—, (C3-C6 cycloalkyl)CH₂O—,hetCyc⁷O—, Ph-O—, or (C1-C6 alkoxy)C1-C6 alkyl-; wherein each of saidC3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R′R″N—where R′ and R″ are independently hydrogen or C1-C6 alkyl;

R⁴ is H or C1-C6 alkyl;

R⁵ is Ar², hetAr³, Ar²CH₂—, hetCyc⁶-CH₂—, hydroxyC1-C6 alkyl-, (C3-C6cycloalkyl)CH₂—, or C1-C6 alkyl optionally substituted with 1-3 fluoros;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, andR^(g)R^(h)N— where R^(g) and R^(h) are independently H or C1-C6 alkyl,or Ar² is phenyl fused to a 6 membered heterocyclic ring having a ringnitrogen atom and optionally substituted with C1-C6 alkyl;

hetAr³ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and(C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros);

hetAr⁴ is pyridin-4(1H)-onyl or pyridin-2(1H)-onyl optionallysubstituted with one or more substituents independently selected fromC1-C6 alkyl and halogen;

hetCyc⁶ is a 5-7 membered heterocyclic ring having 1-3 ring heteroatomsindependently selected from N, O and S; and

hetCyc⁷ is a 5-7 membered heterocyclic ring having 1-3 ring heteroatomsindependently selected from N, O and S.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH.

In one embodiment of Formula I-A, A is CN.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-A, B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkylportion is optionally substituted with a C3-C6 cycloalkylidene ring. Inone embodiment of Formula I-A, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkylor hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In oneembodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-A, Ring D is:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A. In one embodiment, n is 0, 1, 2, 3 or 4. In oneembodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. Inone embodiment, n is 0 and m is 1. In one embodiment, R^(b) is hydroxy,or R^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyl and R^(d) ishydrogen or C1-C6 alkyl.

In one embodiment of Formula I-A, Ring D is:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A. In one embodiment, n is 0, 1, 2, 3 or 4. In oneembodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. Inone embodiment, n is 0 and m is 1. In one embodiment, R^(b) is hydroxy,or R^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyl and R^(d) ishydrogen or C1-C6 alkyl.

In one embodiment of Formula I-A, Ring D is:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A. In one embodiment, n is 0, 1, 2, 3 or 4. In oneembodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. Inone embodiment, n is 0 and m is 1. In one embodiment, R^(b) is hydroxy,or R^(c)R^(d)N— where R^(c) is hydrogen or C1-C6 alkyl and R^(d) ishydrogen or C1-C6 alkyl.

In one embodiment of Formula I-A, E is (d) Ar¹C1-C6 alkyl- wherein saidalkyl portion is optionally substituted with 1-3 fluoros, (e)hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g)is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and Ar¹,hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; and Ring D is:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; and Ring D is:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; and Ring D is:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring Dis

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring Dis

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, and Ring Dis

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring; and Ring D is a piperidin-4-yl ring having thestructure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring; and Ring D is a piperidin-4-yl ring having thestructure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidcnc ring; and Ring D is piperidin-4-yl ring having thestructure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; Ring D is a piperidin-4-yl ring having the structure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (1) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; Ring D is a piperidin-4-yl ring having the structure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; Ring D is a piperidin-4-yl ring having the structure:

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, E is (d) Ar¹C1-C6 alkyl- wherein saidalkyl portion is optionally substituted with 1-3 fluoros, (e)hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where pis 0 or 1 and Ar¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g) is H orC1-C6 alkyl, (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and Ar¹, hetAr² and R^(g)are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (l) Ar¹C(═O)NR^(g)— where R^(g) is H orC1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 andAr¹, hetAr² and R^(g) are as defined for Formula I-A.

In one embodiment, Formula I includes compounds of Formula I-B, wherein:

X¹, X², X³ and X⁴ are independently CH, CF or N, wherein zero, one ortwo of X¹, X², X³ and X⁴ is N;

A is H, CN, Cl, methyl, ethyl or cyclopropyl;

B is

(a) hydrogen,

(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,

(f) (R¹R²N)C1-C6 alkyl- where R¹ and R² are independently selected fromH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(═O)—;

(g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andis optionally substituted with one or more independently selected C1-C6alkyl groups;

(h) (C3-C6 cycloalkyl)C1-C3 alkyl-,

(i) (hetCyc^(a))C1-C3 alkyl-, or

(j) hetCyc^(a);

hetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), andhydroxyC1-C6 alkyl;

Ring D is a saturated 7-8 membered bridged heterocyclic ring having onering heteroatom which is nitrogen;

each R^(a) is independently C1-C6 alkyl (optionally substituted with 1-3fluoros) or hydroxyC1-C6 alkyl;

R^(b) is hydroxy, cyclopropyl, or R^(c)R^(d)N— where R^(c) is hydrogenor C1-C6 alkyl and R^(d) is hydrogen, C1-C6 alkyl or (C1-C6alkoxy)C(═O)—;

n is 0, 1, 2, 3, 4, 5 or 6;

m is 0 or 1;

E is

(a) hydrogen,

(b) hydroxy,

(f) (C1-C6 alkoxy)C1-C6 alkoxy,

(h) hetAr²O—,

(j) hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl,

(n) R⁴R⁵NC(═O)—,

(o) Ar¹NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl, or

(p) hetAr²NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, andR^(e)R^(f)N— where R^(e) and R^(f) are independently H or C1-C6 alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S, or a 9-10 membered bicyclicheteroaryl having 1-2 ring nitrogen atoms, wherein hetAr² is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3fluoros), and (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with1-3 fluoros);

R⁴ is H or C1-C6 alkyl;

R⁵ is Ar², hetAr³ or C1-C6 alkyl optionally substituted with 1-3fluoros;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, andR^(g)R^(h)N— where R^(g) and R^(h) are independently H or C1-C6 alkyl;and

hetAr³ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and(C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros).

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH.

In one embodiment of Formula I-B, A is CN.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-B, B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkylportion is optionally substituted with a C3-C6 cycloalkylidene ring. Inone embodiment of Formula I-B, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkylor hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In oneembodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; and hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring. In one embodiment, B ishydroxyC2-C6 alkyl-.

In one embodiment of Formula I-B, Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(b) and m are as defined forFormula I-B. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment,n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. In oneembodiment, n is 0 and m is 1. In one embodiment, R^(b) is R^(c)R^(d)N—where R^(c) is H or C1-C6 alkyl and R^(d) is H or C1-C6 alkyl. In oneembodiment, R^(b) is R^(c)R^(d)N— where R^(c) and R^(d) are H.

In one embodiment of Formula I-B, E is R⁴R⁵NC(═O)—, where R⁴ and R⁵ areas defined for Formula I-B.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring; and Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(b) and m are as defined forFormula I-B. In one embodiment, m is 0. In one embodiment, m is 1. Inone embodiment, R^(b) is R^(c)R^(d)N— where R^(c) is H or C1-C6 alkyland R^(d) is H or C1-C6 alkyl. In one embodiment, R^(b) is R^(c)R^(d)N—where R^(c) and R^(d) are H.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group, and R^(a), n, R^(b) and m are asdefined for Formula I-A; and E is (n) R⁴R⁵NC(═O)—, where R⁴ and R⁵ areas defined for Formula I-B.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros orhydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidenering; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group; E is (h) hetAr²O—, (j)hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl, (o) Ar¹NR^(g)C(═O)—,where R^(g) is H or C1-C6 alkyl, or (p) hetAr²NR^(g)C(═O)—, where R^(g)is H or C1-C6 alkyl; and R^(b) and m are as defined for Formula I-B. Inone embodiment, m is 0. In one embodiment, m is 1. In one embodiment,R^(b) is R^(c)R^(d)N— where R^(c) is H or C1-C6 alkyl and R^(d) is H orC1-C6 alkyl. In one embodiment, R^(b) is R^(c)R^(d)N— where R^(c) andR^(d) are H.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; B C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group; E is (h) hetAr²O—, (j)hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl, (o) Ar¹NR^(g)C(═O)—,where R^(g) is H or C1-C6 alkyl, or (p) hetAr²NR^(g)C(═O)—, where R^(g)is H or C1-C6 alkyl; and R^(b) and m are as defined for Formula I-B. Inone embodiment, m is 0. In one embodiment, m is 1. In one embodiment,R^(b) is R^(c)R^(d)N— where R^(c) is H or C1-C6 alkyl and R^(d) is H orC1-C6 alkyl. In one embodiment, R^(b) is R^(c)R^(d)N— where R^(c) andR^(d) are H.

In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH; A isCN; B hydroxyC1-C6 alkyl wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring; and Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group; E is (h) hetAr²O—, (j)hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl, (o) Ar¹NR^(g)C(═O)—,where R^(g) is H or C1-C6 alkyl, or (p) hetAr²NR^(g)C(═O)—, where R^(g)is H or C1-C6 alkyl; and R^(b) and m are as defined for Formula I-B. Inone embodiment, m is 0. In one embodiment, m is 1. In one embodiment,R^(b) is R^(c)R^(d)N— where R^(c) is H or C1-C6 alkyl and R^(d) is H orC1-C6 alkyl. In one embodiment, R^(b) is R^(c)R^(d)N— where R^(c) andR^(d) are H.

In one embodiment, Formula I includes compounds of Formula I-C,

wherein:

X¹, X², X³ and X⁴ are independently CH, CF or N, wherein zero, one ortwo of X¹, X², X³ and X⁴ is N;

A is H, CN, Cl, methyl, ethyl or cyclopropyl;

B is

(a) hydrogen,

(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring,

(e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,

(f) (R¹R²N)C1-C6 alkyl- where R¹ and R² are independently selected fromH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6 alkoxy)C(═O)—;

(g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andis optionally substituted with one or more independently selected C1-C6alkyl groups;

(h) (C3-C6 cycloalkyl)C1-C3 alkyl-,

(i) (hetCyc^(a))C1-C3 alkyl-,

(j) hetCyc^(a),

(k) (R¹R²N)C(═O)C1-C6 alkyl- where R¹ and R² are independently selectedfrom H and C1-C6 alkyl, or

(l) (R¹R²N)C(═O)—, where R¹ and R² are independently selected from H andC1-C6 alkyl;

hetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6alkoxy)C(═O)—;

R^(b) is (a) hydroxy, (b) cyclopropyl, (c) hetCyc^(b)CH₂—, (d)R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H orC1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionallysubstituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- or R′R″N—, or saidalkyl portion is optionally substituted with two substituentsindependently selected from R′R″N— and OH, where each R′ and R″ isindependently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH₂)_(n)—where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—, (k) hetCyc^(b)C(═O)NH— or (1)hetAr^(a)C(═O)NH—;

hetCyc^(b) is a 4-6 membered heterocyclic ring, a 7-8 membered bridgedheterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinhetCyc^(b) is optionally substituted with one or more substituentsindependently selected from OH, fluoro, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6alkoxy)C(═O)—, C1-C6 alkoxy, and R′R″N— where R′ and R″ areindependently hydrogen or C1-C6 alkyl;

hetAr^(a) is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S herein hetAr^(a) is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3fluoros);

R^(c) is hydrogen or C1-C6 alkyl;

R^(d) is hydrogen, C1-C6 alkyl (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl;

E is

(a) hydrogen,

(b) hydroxy,

(c) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(d) Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros,

(e) hetAr²C1-C6 alkyl-,

(f) (C1-C6 alkoxy)C1-C6 alkoxy-,

(g) Ar¹O—,

(h) hetAr²O—,

(i) Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl,

(j) hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl,

(k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H orC1-C6 alkyl,

(n) R⁴R⁵NC(═O)—,

(o) Ar¹NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl,

(p) hetAr²NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl,

(r) hetCyc⁵C(═O)—,

(s) R⁴R⁵NC(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(t) (C1-C6 alkyl)SO₂—;

(u) Ar¹(C1-C6 alkyl)C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(v) hetAr⁴C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,

(w) hetAr²—S(═O)—,

(x) (C3-C6 cycloalkyl)CH₂SO₂—,

(y) Ar¹(C1-C6 alkyl)SO₂—,

(z) hetAr²SO₂—,

(aa) Ar¹,

(bb) hetAr²,

(cc) hetCyc⁵,

(dd) C1-C6 alkoxy,

(ee) Ar¹(C1-C6 alkyl)-O—,

(ff) hetAr²(C1-C6 alkyl)-O—,

(gg) hetAr²—O—C1-C6 alkyl-,

(hh) Ar¹(C1-C6 alkyl)NR^(g)— where R^(g) is H or C1-C6 alkyl-,

(ii) hetAr²—S—,

(jj) Ar²SO₂NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H or C1-C6alkyl,

(kk) (C1-C6 alkoxy)C(═O)—,

(ll) (C1-C6 alkyl)NR^(g)C(═O)O— where R^(g) is H or C1-C6 alkyl,

(mm) (C1-C6 alkyl)NR^(g)SO₂— where R^(g) is H or C1-C6 alkyl,

(oo) Q-NR^(h)(C1-C3 alkyl)C(═O)NR^(g)— where R^(g) and R^(h) areindependently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—,

where R^(g) and R^(h) are independently H or C1-C6 alkyl, Q is H, C1-C6alkyl or (C1-C6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,

where R^(g) and R^(h) are independently H or C1-C6 alkyl and Q is H,C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,

where R^(g) is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—, or

(ss) R^(g)R^(h)N— where R^(g) and R^(h) are independently H or C1-C6alkyl;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl,hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO₂—, R^(e)R^(f)N— and(R^(e)R^(f)N)C1-C6 alkyl- where each R^(e) and R^(f) is independently Hor C1-C6 alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S, or a 9-10 membered bicyclicheteroaryl having 1-2 ring nitrogen atoms, wherein hetAr² is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros) and hydroxyC1-C6 alkoxy-;

hetCyc⁵ is a 4-6 membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N, O and S wherein saidheterocyclic ring is optionally substituted with one or moresubstituents independently selected from C1-C6 alkoxy and oxo;

R³ is C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6cycloalkyl)CH₂—, (C3-C6 cycloalkyl)O—, (C3-C6 cycloalkyl)CH₂O—,hetCyc⁷O—, Ph-O—, or (C1-C6 alkoxy)C1-C6 alkyl-; wherein each of saidC3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R′R″N—where R′ and R″ are independently hydrogen or C1-C6 alkyl;

R⁴ is H or C1-C6 alkyl;

R⁵ is Ar², hetAr³, Ar²CH₂—, hetCyc⁶-CH₂—, hydroxyC1-C6 alkyl-, (C3-C6cycloalkyl)CH₂—, or C1-C6 alkyl optionally substituted with 1-3 fluoros;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, andR^(g)R^(h)N— where R^(g) and R^(h) are independently H or C1-C6 alkyl,or Ar² is phenyl fused to a 6 membered heterocyclic ring having a ringnitrogen atom and optionally substituted with C1-C6 alkyl;

hetAr³ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and(C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros);

hetAr⁴ is pyridin-4(1H)-onyl or pyridin-2(1H)-onyl optionallysubstituted with one or more substituents independently selected fromC1-C6 alkyl and halogen;

hetCyc⁶ is a 5-7 membered heterocyclic ring having 1-3 ring heteroatomsindependently selected from N, O and S; and

hetCyc⁷ is a 5-7 membered heterocyclic ring having 1-3 ring heteroatomsindependently selected from N, O and S.

In one embodiment of Formula I-C, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-C, A is CN.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-C, B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkylportion is optionally substituted with a C3-C6 cycloalkylidene ring. Inone embodiment of Formula I-C, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkylor hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In oneembodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-C, E is (d) Ar¹C1-C6 alkyl- wherein saidalkyl portion is optionally substituted with 1-3 fluoros, (e)hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g)is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,(1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R^(g), Ar¹ andhetAr² are as defined for Formula I-C.

In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros; and E is (d) Ar¹C1-C6 alkyl- wherein saidalkyl portion is optionally substituted with 1-3 fluoros, (e)hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g)is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,(l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R^(g), Ar¹ andhetAr² are as defined for Formula I-C.

In one embodiment of Formula I-C, A is CN; B is hydroxyC2-C6 alkyl-optionally substituted with a C3-C6 cycloalkylidene ring; and E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros, (e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i)Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and Ar¹,hetAr² and R^(g) are as defined for Formula I-C.

In one embodiment of Formula I-C, R^(b) is (c) hetCyc^(b)CH₂— wherehetCyc^(b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc^(b) isoptionally substituted with one or more substituents independentlyselected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl-(optionally substituted with 1-3 fluoros),and (C1-C6 alkoxy)C1-C6 alkyl-, (e) R^(c)R^(d)N—, or (f)R^(c)R^(d)NCH₂—; R^(c) is hydrogen or C1-C6 alkyl; and R^(d) ishydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—,(R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) are independently H orC1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) areindependently H or C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, orhetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclic ring having aring heteroatom selected from N and O and optionally substituted withC1-C6 alkyl.

In one embodiment of Formula I-C, R^(b) is hetCyc^(b)CH₂— wherehetCyc^(b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc^(b) isoptionally substituted with one or more substituents independentlyselected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl-(optionally substituted with 1-3 fluoros),and (C1-C6 alkoxy)C1-C6 alkyl-.

In one embodiment of Formula I-C, R^(b) is R^(c)R^(d)N—; R^(c) ishydrogen or C1-C6 alkyl; and R^(d) is hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl(optionally substituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—,(C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-C, R^(b) is R^(c)R^(d)NCH₂—; R ishydrogen or C1-C6 alkyl; and R^(d) is hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl(optionally substituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—,(C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-C, A is CN, B is hydroxyC2-C6 alkyl-optionally substituted with a C3-C6 cycloalkylidene ring; E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros, (e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i)Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³,R^(g), Ar¹ and hetAr² are as defined for Formula I-C; and R^(b) is (c)hetCyc^(b)CH₂— where hetCyc^(b) is a 4-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinhetCyc^(b) is optionally substituted with one or more substituentsindependently selected from OH, fluoro, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), and (C1-C6 alkoxy)C1-C6 alkyl-.

In one embodiment of Formula I-C, A is CN, B is hydroxyC2-C6 alkyl-optionally substituted with a C3-C6 cycloalkylidene ring; E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros, (e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i)Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³,R^(g), Ar¹ and hetAr² are as defined for Formula I-C; R^(b) is (e)R^(c)R^(d)N—; R^(c) is hydrogen or C1-C6 alkyl; and R^(d) is hydrogen,C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—,(R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) are independently H orC1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) areindependently H or C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, orhetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclic ring having aring heteroatom selected from N and O and optionally substituted withC1-C6 alkyl.

In one embodiment of Formula I-C, A is CN, B is hydroxyC2-C6 alkyl-optionally substituted with a C3-C6 cycloalkylidene ring; E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros, (e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i)Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R,Ar¹ and hetAr² are as defined for Formula I-C; R^(b) is (f)R^(c)R^(d)NCH₂—; R^(c) is hydrogen or C1-C6 alkyl; and R^(d) ishydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—,(R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) are independently H orC1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) areindependently H or C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, orhetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclic ring having aring heteroatom selected from N and O and optionally substituted withC1-C6 alkyl.

In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros; E is (d) Ar¹C1-C6 alkyl- wherein saidalkyl portion is optionally substituted with 1-3 fluoros, (e)hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g)is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,(l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R^(g), Ar¹ andhetAr² are as defined for Formula I-C; and R^(b) is (c) hetCyc^(b)CH₂—where hetCyc^(b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc^(b) isoptionally substituted with one or more substituents independentlyselected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl- (optionally substituted with 1-3 fluoros),and (C1-C6 alkoxy)C1-C6 alkyl-.

In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros; E is (d) Ar¹C1-C6 alkyl- wherein saidalkyl portion is optionally substituted with 1-3 fluoros, (e)hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g)is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,(l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R^(g), Ar¹ andhetAr² are as defined for Formula I-C; R^(b) is (e) R^(c)R^(d)N—; R^(c)is hydrogen or C1-C6 alkyl; and R^(d) is hydrogen, C1-C6 alkyl(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros; E is (d) Ar¹C1-C6 alkyl- wherein saidalkyl portion is optionally substituted with 1-3 fluoros, (e)hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g)is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,(l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R^(g), Ar¹ andhetAr² are as defined for Formula I-C; R^(b) is (f) R^(c)R^(d)NCH₂—;R^(c) is hydrogen or C1-C6 alkyl; and R^(d) is hydrogen, C1-C6 alkyl(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring; E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g) is H orC1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, (l)Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R, Ar¹ and hetAr²are as defined for Formula I-C; and R^(b) is (c) hetCyc^(b)CH₂— wherehetCyc^(b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc^(b) isoptionally substituted with one or more substituents independentlyselected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl- (optionally substituted with 1-3 fluoros),and (C1-C6 alkoxy)C1-C6 alkyl-.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring; E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g) is H orC1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, (l)Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R, Ar¹ and hetAr²are as defined for Formula I-C; R^(b) is (e) R^(c)R^(d)N—; R is hydrogenor C1-C6 alkyl; and R^(d) is hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl(optionally substituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—,(C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring; E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g) is H orC1-C6 alkyl, (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, (l)Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R, Ar¹ and hetAr²are as defined for Formula I-C; R^(b) is (f) R^(c)R^(d)NCH₂—; R^(c) ishydrogen or C1-C6 alkyl; and R^(d) is hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—, hydroxyC1-C6 alkyl(optionally substituted with 1-3 fluoros), (hydroxyC1-C6 alkyl)C(═O)—,(C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) areindependently H or C1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m)and R^(n) are independently H or C1-C6 alkyl, PhCH₂—, (C1-C6alkoxy)C1-C6 alkyl-, or hetCyc^(c) where hetCyc^(c) is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O andoptionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros, (e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i)Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³,R^(g), Ar¹ and hetAr² are as defined for Formula I-C; and R^(b) is (c)hetCyc^(b)CH₂— where hetCyc^(b) is a 4-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinhetCyc^(b) is optionally substituted with one or more substituentsindependently selected from OH, fluoro, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl- (optionallysubstituted with 1-3 fluoros), and (C1-C6 alkoxy)C1-C6 alkyl-.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros, (e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i)Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³,R^(g), Ar¹ and hetAr² are as defined for Formula I-C; R^(b) is (e)R^(c)R^(d)N—; R^(c) is hydrogen or C1-C6 alkyl; and R^(d) is hydrogen,C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—,(R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) are independently H orC1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) areindependently H or C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, orhetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclic ring having aring heteroatom selected from N and O and optionally substituted withC1-C6 alkyl.

In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros, (e) hetAr²C1-C6 alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i)Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl, (1) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)—, where p is 0 or 1 and R³, R,Ar¹ and hetAr² are as defined for Formula I-C; R^(b) is (f)R^(c)R^(d)NCH₂—; R^(c) is hydrogen or C1-C6 alkyl; and R^(d) ishydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C(═O)—, hydroxyC1-C6 alkyl (optionally substituted with 1-3fluoros), (hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—,(R^(k)R^(l)N)C1-C6 alkyl- where R^(k) and R^(l) are independently H orC1-C6 alkyl, R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) areindependently H or C1-C6 alkyl, PhCH₂—, (C1-C6 alkoxy)C1-C6 alkyl-, orhetCyc^(c) where hetCyc^(c) is a 4-6 membered heterocyclic ring having aring heteroatom selected from N and O and optionally substituted withC1-C6 alkyl.

In one embodiment, Formula I includes compounds of Formula I-D, wherein:

X¹ and X³ are N, and X² and X⁴ are CH or CF; and A, B, E, R^(a), R^(b),m and n are as defined for Formula I.

In one embodiment of Formula I-D, A is CN.

In one embodiment of Formula I-D, B is (c) hydroxyC2-C6 alkyl- whereinthe alkyl portion is optionally substituted with a C3-C6 cycloalkylidenering, (f) (R¹R²N)C1-C6 alkyl- where R¹ and R² are independently selectedfrom H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6 alkoxy)C(═O)—, (g)hetAr¹C1-C3 alkyl-, where hetAr^(i) is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andis optionally substituted with one or more independently selected C1-C6alkyl substituents, or (i) (hetCyc^(a))C1-C3 alkyl-; and hetCyc^(a) is a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O and optionally substituted with one or moresubstituents independently selected from OH, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl, halogen, (C1-C6alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(═O)—.

In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring, (f) (R¹R²N)C1-C6 alkyl- where R¹ and R² areindependently selected from H, C1-C6 alkyl (optionally substituted with1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6alkoxy)C(═O)—, (g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and is optionally substituted with one or more independentlyselected C1-C6 alkyl substituents, or (i) (hetCyc^(a))C1-C3 alkyl-; andhetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6alkoxy)C(═O)—.

In one embodiment of Formula I-D, E is (l) Ar¹C(═O)NR^(g)— where R^(g)is H or C1-C6 alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or1 and R^(g) is H or C1-C6 alkyl.

In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring, (f) (R¹R²N)C1-C6 alkyl- where R¹ and R² areindependently selected from H, C1-C6 alkyl (optionally substituted with1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6alkoxy)C(═O)—, (g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and is optionally substituted with one or more independentlyselected C1-C6 alkyl substituents, or (i) (hetCyc^(a))C1-C3 alkyl-;hetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6alkoxy)C(═O)—; and E is (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) isH or C1-C6 alkyl.

In one embodiment of Formula I-D, m is 1; and n is 0 or 1.

In one embodiment of Formula I-D, m is 1; and n is 0.

In one embodiment of Formula I-D, m is 1; n is 0; and R^(b) is hydroxy.

In one embodiment of Formula I-D, m is 0; and n is 0 or 1.

In one embodiment of Formula I-D, m is 0; n is 0 or 1; and R^(a) isC1-C6 alkyl optionally substituted with 1-3 fluoros.

In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring, (f) (R¹R²N)C1-C6 alkyl- where R¹ and R² areindependently selected from H, C1-C6 alkyl (optionally substituted with1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6alkoxy)C(═O)—, (g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and is optionally substituted with one or more independentlyselected C1-C6 alkyl substituents, or (i) (hetCyc^(a))C1-C3 alkyl-;hetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6alkoxy)C(═O)—; E is (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H orC1-C6 alkyl; m is 0 or 1; n is 0 or 1; R^(a) is C1-C6 alkyl optionallysubstituted with 1-3 fluoros; and R^(b) is hydroxy. In one embodiment, mis 1, n is 0, and R^(b) is hydroxy. In one embodiment, m is 0, n is 1,and R^(b) is C1-C6 alkyl optionally substituted with 1-3 fluoros.

In one embodiment of Formula I-D, Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group.

In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring, (f) (R¹R²N)C1-C6 alkyl- where R¹ and R² areindependently selected from H, C1-C6 alkyl (optionally substituted with1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6alkoxy)C(═O)—, (g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and is optionally substituted with one or more independentlyselected C1-C6 alkyl substituents, or (i) (hetCyc^(a))C1-C3 alkyl-;hetCyc^(a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromOH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo and (C1-C6alkoxy)C(═O)—; E is (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,or (m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H orC1-C6 alkyl; m is 0 or 1; n is 0 or 1; R^(a) is C1-C6 alkyl optionallysubstituted with 1-3 fluoros; and Ring D is

wherein the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴, the asterisk indicates the point ofattachment of Ring D to the E group. In one embodiment, m is 1, n is 0,and R^(b) is hydroxy. In one embodiment, m is 0, n is 1, and R^(b) isC1-C6 alkyl optionally substituted with 1-3 fluoros.

In one embodiment, compounds of Formula I include compounds of FormulaI-E:

where E is (k) R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl; R^(b) is(c) hetCyc^(b)CH₂—; and R³, A, B, X¹, X², X³ and X⁴ are as defined forFormula I.

In one embodiment of Formula I-E, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-E, A is CN.

In one embodiment of Formula I-E, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-E, B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros.

In one embodiment of Formula I-E, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros.

In one embodiment, compounds of Formula I include compounds of FormulaI-F

where E is (d) Ar¹C1-C6 alkyl- wherein said alkyl portion is optionallysubstituted with 1-3 fluoros or (e) hetAr²C1-C6 alkyl-; R^(b) is (a)hydroxy, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) areindependently H or C1-C6 alkyl, or (e) R^(c)R^(d)N—; and X¹, X¹, X³, X⁴,A, B, Ar¹, hetAr², R^(c) and R^(d) are as defined for Formula I.

In one embodiment of Formula I-F, X¹ is N; and X², X³ and X⁴ are CH. Inone embodiment, E is (d) Ar¹C1-C6 alkyl- wherein said alkyl portion isoptionally substituted with 1-3 fluoros. In one embodiment, E is (e)hetAr²C1-C6 alkyl-.

In one embodiment of Formula I-F, A is CN. In one embodiment, E is (d)Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros. In one embodiment, E is (e) hetAr²C1-C6 alkyl-.

In one embodiment of Formula I-F, B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkylportion is optionally substituted with a C3-C6 cycloalkylidene ring. Inone embodiment of Formula I-F, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.In one embodiment, E is (d) Ar¹C1-C6 alkyl- wherein said alkyl portionis optionally substituted with 1-3 fluoros. In one embodiment, E is (e)hetAr²C1-C6 alkyl-.

In one embodiment of Formula I-F, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkylor hydroxyC2-C6 alkyl-. In one embodiment, E is (d) Ar¹C1-C6 alkyl-wherein said alkyl portion is optionally substituted with 1-3 fluoros.In one embodiment, E is (e) hetAr²C1-C6 alkyl-.

In one embodiment of Formula I-F, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring; and R^(b) is (a) hydroxy. In oneembodiment, E is (d) Ar¹C1-C6 alkyl- wherein said alkyl portion isoptionally substituted with 1-3 fluoros. In one embodiment, E is (e)hetAr²C1-C6 alkyl-.

In one embodiment of Formula I-F, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring; and R^(b) is (d)R′R^(j)NC(═O)CH₂OCH₂— where R^(i) and R^(j) are independently H or C1-C6alkyl. In one embodiment, E is (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros. In one embodiment, Eis (e) hetAr²C1-C6 alkyl-.

In one embodiment of Formula I-F, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring; and R^(b) is (e) R^(c)R^(d)N— whereR^(c) and R^(d) are as defined for Formula I. In one embodiment, E is(d) Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros. In one embodiment, E is (e) hetAr²C1-C6 alkyl-.

In one embodiment of Formula I-F, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, orhydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring; and R^(b) is (e) R^(c)R^(d)N— whereR^(c) and R^(d) are as defined for Formula I. In one embodiment, E is(d) Ar¹C1-C6 alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros. In one embodiment, E is (e) hetAr²C1-C6 alkyl-.

In one embodiment, compounds of Formula I include compounds of FormulaI-G

where E is (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H or C1-C6alkyl; R^(a) is C1-C6 alkyl optionally substituted with 1-3 fluoros; andAr¹, hetAr², X¹, X¹, X³, X⁴, A and B are as defined for Formula I.

In one embodiment of Formula I-G, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-G, A is CN.

In one embodiment of Formula I-G, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkylportion is optionally substituted with a C3-C6 cycloalkylidene ring, (f)(R¹R²N)C1-C6 alkyl- where R¹ and R² are independently selected from H,C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6 alkoxy)C(═O)—, (g)hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andis optionally substituted with one or more independently selected C1-C6alkyl substituents, or (i) (hetCyc^(a))C1-C3 alkyl-, where hetCyc^(a) isas defined for Formula I.

In one embodiment of Formula I-G, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In oneembodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-G, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.

In one embodiment of Formula I-G, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (R¹R²N)C1-C6 alkyl- where R¹ and R² are independentlyselected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros),(C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkyl)C(═O)— and (C1-C6alkoxy)C(═O)—.

In one embodiment of Formula I-G, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and is optionally substituted with one or more independentlyselected C1-C6 alkyl substituents.

In one embodiment of Formula I-G, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (hetCyc^(a))C1-C3 alkyl-, where hetCyc^(a) is as definedfor Formula I.

In one embodiment, compounds of Formula I include compounds of FormulaI-H

where E is (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl or (m)hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H or C1-C6alkyl; R^(b) is (a) hydroxy, (c) hetCyc^(b)CH₂—, (f) R^(c)R^(d)NCH₂—,(g) C1-C6 alkoxy-, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; and Ar¹, hetAr²,X¹, X¹, X³, X⁴, A, B, hetCyc^(b), R^(c) and R^(d) are as defined forFormula I.

In one embodiment of Formula I-H, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-H, A is CN.

In one embodiment of Formula I-H, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In oneembodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (a) hydroxy.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (c) hetCyc^(b)CH₂—.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (f) R^(c)R^(d)NCH₂—.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (g) C1-C6 alkoxy-.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—.

In one embodiment, compounds of Formula I include compounds of FormulaI-I

where E is (n) R⁴R⁵NC(═O)—; R^(b) is (c) hetCyc^(b)CH₂—, (f)R^(c)R^(d)NCH₂— or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; and X¹, X¹, X³, X⁴,A, B, hetCyc^(b), R^(c), R^(d), R⁴ and R⁵ are as defined for Formula I.

In one embodiment of Formula I-I, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-I, A is CN.

In one embodiment of Formula I-I, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-I, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In oneembodiment, B is C1-C6 alkyl.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (c) hetCyc^(b)CH₂—.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (f) R^(c)R^(d)NCH₂—.

In one embodiment of Formula I-H, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and R^(b)is (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—.

In one embodiment, compounds of Formula I include compounds of FormulaI-I

where E is (n) R⁴R⁵NC(═O)—; R^(b) is (c) hetCyc^(b)CH₂—, (f)R^(c)R^(d)NCH₂—, or (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—; and X¹, X¹, X³,X⁴, A, B, R⁴, R⁵, hetCyc^(b), R and R^(d) are as defined for Formula I.

In one embodiment of Formula I-I, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-I, A is CN.

In one embodiment of Formula I-I, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros or (i) (hetCyc^(a))C1-C3 alkyl-.

In one embodiment of Formula I-I, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

In one embodiment of Formula I-I, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (i) (hetCyc^(a))C1-C3 alkyl-.

In one embodiment of Formula I-I, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i)(hetCyc^(a))C1-C3 alkyl-; and R^(b) is (c) hetCyc^(b)CH₂—.

In one embodiment of Formula I-I, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i)(hetCyc^(a))C1-C3 alkyl-; and R^(b) is (f) R^(c)R^(d)NCH₂—.

In one embodiment of Formula I-I, X¹ is N; X², X³ and X⁴ are CH; A isCN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i)(hetCyc^(a))C1-C3 alkyl-; and R^(b) is (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—.

In one embodiment, compounds of Formula I include compounds of FormulaI-J

where E is (n) R⁴R⁵NC(═O)—; R^(a) is C1-C6 alkyl optionally substitutedwith 1-3 fluoros; and X¹, X¹, X³, X⁴, A, B, R⁴ and R⁵ are as defined forFormula I.

In one embodiment of Formula I-J, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-J, A is CN.

In one embodiment of Formula I-J, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-J, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.

In one embodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl- whereinthe alkyl portion is optionally substituted with a C3-C6 cycloalkylidenering. In one embodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl.

In one embodiment of Formula I-J, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. Inone embodiment, B is (b) C1-C6 alkyl.

In one embodiment of Formula I-J, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion isoptionally substituted with a C3-C6 cycloalkylidene ring. In oneembodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl-.

In one embodiment, compounds of Formula I include compounds of FormulaI-K where E is (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl or(m) hetAr²C(═O)NR^(g)(CH₂)_(p)— where p is 0 or 1 and R^(g) is H orC1-C6 alkyl; Ring D is

where the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴; R^(a) is C1-C6 alkyl optionallysubstituted with 1-3 fluoros; and X¹, X¹, X³, X⁴, A, B, Ar¹ and hetAr²are as defined for Formula I.

In one embodiment of Formula I-K, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-K, A is CN.

In one embodiment of Formula I-K, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-K, B is (a) hydrogen, (b) C1-C6 alkyloptionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- whereinthe alkyl portion is optionally substituted with a C3-C6 cycloalkylidenering, (f) (R¹R²N)C1-C6 alkyl- where R¹ and R² are independently selectedfrom H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(═O)—, (g) hetAr¹C1-C3 alkyl-,where hetAr¹ is a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and is optionallysubstituted with one or more independently selected C1-C6 alkylsubstituents, or (i) (hetCyc^(a))C1-C3 alkyl-, where hetCyc^(a) is asdefined for Formula I.

In one embodiment of Formula I-K, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (a) hydrogen.

In one embodiment of Formula I-K, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

In one embodiment of Formula I-K, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion isoptionally substituted with a C3-C6 cycloalkylidene ring.

In one embodiment of Formula I-K, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (f) (R¹R²N)C1-C6 alkyl- where R¹ and R² are independentlyselected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros),(C1-C6 alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(═O)—

In one embodiment of Formula I-K, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and is optionally substituted with one or more independentlyselected C1-C6 alkyl substituents.

In one embodiment of Formula I-K, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (i) (hetCyc^(a))C1-C3 alkyl-, where hetCyc^(a) is asdefined for Formula I.

In one embodiment, compounds of Formula I include compounds of FormulaI-L where E is (g) Ar¹O— or (h) hetAr²—O—; Ring D is

where the wavy line indicates the point of attachment of Ring D to thering comprising X¹, X², X³ and X⁴; and X¹, X¹, X³, X⁴, A, B, Ar¹ andhetAr² are as defined for Formula I.

In one embodiment of Formula I-L, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-L, A is CN.

In one embodiment of Formula I-L, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-L, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkylportion is optionally substituted with a C3-C6 cycloalkylidene ring, (i)(hetCyc^(a))C1-C3 alkyl- or (k) (R¹R²N)C(═O)C1-C6 alkyl- where R¹ and R²are independently selected from H and C1-C6 alkyl.

In one embodiment of Formula I-L, X¹ is N; X², X³ X⁴ are CH; and A isCN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

In one embodiment of Formula I-L, X¹ is N; X², X³ X⁴ are CH; and A isCN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion isoptionally substituted with a C3-C6 cycloalkylidene ring.

In one embodiment of Formula I-L, X¹ is N; X², X³ X⁴ are CH; and A isCN; and B is (i) (hetCyc^(a))C1-C3 alkyl- or (k) (R¹R²N)C(═O)C1-C6alkyl- where R¹ and R² are independently selected from H and C1-C6alkyl.

In one embodiment, compounds of Formula I include compounds of FormulaI-M

where E is (k) R³C(═O)NR^(g) where R^(g) is H or C1-C6 alkyl; R^(b) is(a) hydroxy; and X¹, X¹, X³, X⁴, R³, A and B, are as defined for FormulaI.

In one embodiment of Formula I-M, X¹ is N; and X², X³ and X⁴ are CH.

In one embodiment of Formula I-M, A is CN.

In one embodiment of Formula I-M, X¹ is N; X², X³ and X⁴ are CH; and Ais CN.

In one embodiment of Formula I-M, B is (b) C1-C6 alkyl optionallysubstituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.

In one embodiment of Formula I-M, X¹ is N; X², X³ and X⁴ are CH; A isCN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. Inone embodiment, B is (b) C1-C6 alkyl.

In one embodiment of Formula I-M, R³ is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), C1-C6 alkoxy, or C3-C6 cycloalkyl,wherein said C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH, or R′R″N—where R′ and R″ are independently hydrogen or C1-C6 alkyl.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I. Non-limiting examples ofpharmaceutically acceptable salts of compounds of Formula I includemonohydrochloride, dihydrochloride, trifluoroacetic acid, anddi-trifluoroacetic acid salts. In one embodiment, compounds of Formula Iinclude trifluoroacetic acid and dihydrochloride salts.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention. Forexample, compounds of Formula I and salts thereof can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like.

In one embodiment, the compounds of Formula I include the compounds ofExamples 1-819 and stereoisomers and pharmaceutically acceptable saltsand solvates thereof. In one embodiment, the compounds of Examples 1-819are in the free base form. In one embodiment, the compounds of Examples1-819 are dihydrochloride or trifluoroacetic acid salts.

The term “pharmaceutically acceptable” indicates that the compound, orsalt or composition thereof is compatible chemically and/ortoxicologically with the other ingredients comprising a formulationand/or the patient being treated therewith.

Compounds provided herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. That is, an atom, in particular when mentioned in relation toa compound according to Formula I, comprises all isotopes and isotopicmixtures of that atom, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, when hydrogen is mentioned, it is understood to referto ¹H, ²H, ³H or mixtures thereof; when carbon is mentioned, it isunderstood to refer to ¹¹C, ¹²C, ¹³C ¹⁴C or mixtures thereof; whennitrogen is mentioned, it is understood to refer to ¹³N, ¹⁴N, ¹⁵N ormixtures thereof; when oxygen is mentioned, it is understood to refer to¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluoro ismentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof.The compounds provided herein therefore also comprise compounds with oneor more isotopes of one or more atoms, and mixtures thereof, includingradioactive compounds, wherein one or more non-radioactive atoms hasbeen replaced by one of its radioactive enriched isotopes. Radiolabeledcompounds are useful as therapeutic agents, e.g., cancer therapeuticagents, research reagents, e.g., assay reagents, and diagnostic agents,e.g., in vivo imaging agents. All isotopic variations of the compoundsprovided herein, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

For illustrative purposes, Schemes 1-6 show general methods forpreparing the compounds provided herein as well as key intermediates.For a more detailed description of the individual reaction steps, seethe Examples section below. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the inventivecompounds. Although specific starting materials and reagents aredepicted in the Schemes and discussed below, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a general scheme for the synthesis of compound X where Ais CN, and B, X¹, X², X³, X⁴, Ring D, R^(a), R^(b), n, m and E are asdefined for Formula I.

Compound 2 is obtained by treating 3-bromo-5-methoxypyridine (compound1), which is commercially available, withO-(mesitylsulfonyl)hydroxylamine. The O-mesitylsulfonylhydroxylamine maybe prepared as described in Mendiola, J., et al., Org. Process Res. Dev.2009, 13(2), 263-267. Compound 2 may be reacted with ethyl propiolate toprovide a mixture of compounds 3A and 3B, which typically are obtainedin a ratio of approximately 2:1 to 9:1, respectively. The mixture ofcompounds 3A and 3B may be treated with 48% HBr at elevatedtemperatures, followed by recrystallization or chromatographypurifications, to isolate compound 4A as the minor isomer and compound4B as the major isomer. After isolation, compound 4A may be treated withPOCl₃ to provide compound 5. The formyl group may be converted to anoxime group using NH₂OH to provide compound 6. The oxime group may beconverted to a nitrile group using acetic anhydride to provide compound7. The methoxy group of compound 7 may be converted to a hydroxy groupby treating compound 7 with aluminum trichloride to provide compound 8.

When group B is hydrogen, compound 12 may be prepared by couplingcompound 8 with the corresponding boronic ester compound 10 (where RingD, E, X¹, X², X³ and X⁴ are as defined for Formula I; Z is—B(OR^(x))(OR^(y)) and R^(z) and R^(y) are H or (1-6C)alkyl, or R^(x)and R^(y) together with the atoms to which they are connected form a 5-6membered ring optionally substituted with 1-4 substituents selected from(C1-C3 alkyl)) to provide compound 11a using appropriatepalladium-catalyzed cross-coupling reaction conditions, e.g., Suzukicoupling reaction conditions (for example, a palladium catalyst andoptionally a ligand in the presence of an inorganic base, for example,Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevated temperatures), wherein ifRing D of compound 10 is substituted with an R^(b) substituent that isR^(c)R^(d)N— wherein one or both of R^(c) and R^(d) is hydrogen, thenitrogen atom of R^(b) may be protected with an appropriate aminoprotecting group prior to coupling. The amino protecting group ifpresent on a substituent of Ring D of compound 11a may be removed understandard conditions (for example, a Boc group may be removed by treatingcompound 11a to acidic conditions, e.g., HCl) to provide compound 12where B is hydrogen. Alternatively, the E group may be functionalized(i.e., reacted or treated with an appropriate reagent) under standardconditions such as described below to provide compound 12 where B ishydrogen and E is as defined for Formula I except that E is nothydrogen.

Alternatively, when group B is as defined for Formula I other thanhydrogen, Compound 11a may be reacted with a reagent such as C1-C6alkyl-OH, (C1-C6 alkoxy)C1-C6 alkyl-OH optionally substituted with 1-3fluoros, hetAr¹C1-C3 alkyl-OH, (C3-C6 cycloalkyl)C1-C3 alkyl-OH,(hetCyc^(a))C1-C3 alkyl-OH, hetCyc^(a)OH or hetCyc^(a)C(═O)C1-C6alkyl-OH, where hetAr¹ and hetCyc^(a) are as defined for Formula I,under Mitsunobu reaction conditions (PPh₃ and diisopropylazodicarboxylate) to provide compound 11. Compound 12 may then beprepared from compound 11 as described above.

Alternatively, when group B is as defined for Formula I other thanhydrogen, compound 9 may be prepared by reacting compound 8 with areagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros,hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein thealkyl portion is optionally substituted with a C3-C6 cycloalkylidenering, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3fluoros, (R¹R²N)C1-C6 alkyl-X, hetAr¹C1-C3 alkyl-X, (C3-C6cycloalkyl)C1-C3 alkyl-X, (hetCyc^(a))C1-C3 alkyl-X, hetCyc^(a)-X, orhetCyc^(a)C(═O)C1-C6 alkyl-X, where R¹, R², hetAr¹, and hetCyc^(a) areas defined for Formula I and X is a leaving atom or group (such as ahalide or triflate), wherein each of said reagents is optionallysubstituted with a protecting group (e.g., a t-butyldimethylsilyl groupif the B group has one or two additional hydroxy groups), in thepresence of a base (for example, an alkali metal carbonate, such aspotassium carbonate). For example, when B is C1-C6 alkyl optionallysubstituted with 1-3 fluoros, compound may be prepared by reactingcompound 8 with a C1-C6 alkyl-X, where X is a halogen such as Br or Cl,or a leaving group such as triflate. Compound 11 may then be prepared bycoupling compound 9 with the corresponding boronic ester compound 10using appropriate palladium-catalyzed cross-coupling reactionconditions, e.g., Suzuki coupling reaction conditions (for example, apalladium catalyst and optionally a ligand in the presence of aninorganic base, for example, Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevatedtemperatures), wherein if Ring D of compound 10 is substituted with anR^(b) substituent that is R^(c)R^(d)N— wherein one or both of R andR^(d) is hydrogen, the nitrogen atom of R^(b) may be protected with anappropriate amino protecting group prior to coupling. Compound 12 maythen be prepared from compound 11 as described above.

Scheme 2 shows another general scheme for the synthesis of compound 17where A is CN, and B, X¹, X², X³, X⁴, Ring D, R^(a), R^(b), n, m and Eare as defined for Formula I.

Compound 9 (prepared, e.g., as described in Scheme 1) in which B is asdefined for Formula I, may be coupled with compound 13 (where X¹, X², X³and X⁴ are as defined for Formula I; L² is a leaving group such as atriflate or halide); Z is —B(OR^(x))(OR^(y)) and R^(z) and R^(y) are Hor (1-6C)alkyl, or R^(x) and R^(y) together with the atoms to which theyare connected form a 5-6 membered ring optionally substituted with 1-4substituents selected from (C1-C3 alkyl)), using appropriatepalladium-catalyzed cross-coupling reaction conditions, e.g., Suzukicoupling reaction conditions (for example, a palladium catalyst andoptionally a ligand in the presence of an inorganic base, for example,Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevated temperatures) to providecompound 14. Compound 16 may be prepared by coupling compound 14 withcompound 15 under appropriate S_(N)Ar conditions (for example,optionally in the presence of a base such as K₂CO₃ and at elevatedtemperature), wherein if Ring D of compound 15 is substituted with anR^(b) substituent that is R^(c)R^(d)N— wherein one or both of R^(c) andR^(d) is hydrogen, the nitrogen atom of R^(b) may be protected with anappropriate amino protecting group prior to coupling. The aminoprotecting group if present may then be removed under standardconditions (for example, a Boc group may be removed by treating compound1 to acidic conditions, e.g., HCl) to provide compound 17 where E is H.

Alternatively, the E group may be functionalized (i.e., reacted ortreated with an appropriate reagent) under standard conditions such asdescribed below to provide compound 17 where E is as defined for FormulaI except that E is not H.

Scheme 3 shows a general scheme for the synthesis of Compound 21 where Ais H, and B, X¹, X², X³, X⁴, Ring D, R^(a), R^(b), n, m and E are asdefined for Formula I.

Compound 18 may be prepared by coupling compound 4A (prepared e.g., asdescribed in Scheme 1) with the corresponding boronic ester compound 10(where Ring D, X¹, X², X³ and X⁴ are as defined for Formula I; Z is—B(OR^(X))(OR^(y)) and R^(z) and R^(y) are H or (1-6C)alkyl, or R^(x)and R^(y) together with the atoms to which they are connected form a 5-6membered ring optionally substituted with 1-4 substituents selected from(C1-C3 alkyl)) using appropriate palladium-catalyzed cross-couplingreaction conditions, e.g., Suzuki coupling reaction conditions (forexample, a palladium catalyst and optionally a ligand in the presence ofan inorganic base, for example, Pd(PPh₃)₄ and Na₂CO₃ in dioxane atelevated temperatures), wherein if Ring D of compound 10 is substitutedwith an R^(b) substituent that is R^(c)R^(d)N— wherein one or both of Rand R^(d) is hydrogen, the nitrogen atom of R^(b) may be protected withan appropriate amino protecting group prior to coupling. Compound 19 maybe prepared by treating compound 18 with aluminum trichloride.

When B is as defined for Formula I other than hydrogen, compound 20 maybe prepared by reacting compound 19 with a reagent such as C1-C6 alkyl-Xoptionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X whereinthe alkyl portion is optionally substituted with a C3-C6 cycloalkylidenering, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)C1-C6alkyl-X optionally substituted with 1-3 fluoros, (R¹R²N)C1-C6 alkyl-X,hetAr¹C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc^(a))C1-C3alkyl-X, hetCyc^(a)-X or hetCyc^(a)C(═O)C1-C6 alkyl-X, where R¹, R²,hetAr¹, and hetCyc^(a) are as defined for Formula I and X is a leavingatom or group (such as a halide or triflate), wherein each of saidreagents is optionally substituted with a protecting group (e.g., at-butyldimethylsilyl group if B has one or two additional hydroxygroups). For example, when B is C1-C6 alkyl optionally substituted with1-3 fluoros, compound may be prepared by reacting compound 19 with C1-C6alkyl-X, where X is a halogen such as Br or Cl, or a leaving group suchas triflate. Compound 21 may then be prepared from compound 20. If RingD comprises a substituent having an amino protecting group, the aminoprotecting group may be removed under standard conditions (for example,a Boc group may be removed by treating compound 20 to acidic conditions,e.g., HCl) to provide compound 21 where E is H.

Alternatively, the E group of compound 20 may be functionalized (i.e.,reacted or treated with an appropriate reagent) under standardconditions such as described below to provide compound 21 where E is asdefined for Formula I except that E is not H.

Alternatively, when group B is hydrogen, compound 21 may be preparedfrom compound 19 according to the deprotection and optionalfunctionalization steps described herein.

Scheme 4 shows an alternative general scheme for the synthesis ofCompound 21 where A is H, and B, X¹, X², X³, X⁴, Ring D, R^(a), R^(b),n, m and E are as defined for Formula I.

Compound 22 may be prepared by treating compound 4A (prepared e.g., asdescribed in Scheme 1) with aluminum trichloride.

When group B is hydrogen, compound 19 may be prepared by couplingcompound 22 with the corresponding boronic ester compound 10 (where RingD, X¹, X², X³ and X⁴ are as defined for Formula I; Z is—B(OR^(x))(OR^(y)) and R^(z) and R^(y) are H or (1-6C)alkyl, or R^(x)and R^(y) together with the atoms to which they are connected form a 5-6membered ring optionally substituted with 1-4 substituents selected from(C1-C3 alkyl)) using appropriate palladium-catalyzed cross-couplingreaction conditions, e.g., Suzuki coupling reaction conditions (forexample, a palladium catalyst and optionally a ligand in the presence ofan inorganic base, for example, Pd(PPh₃)₄ and Na₂CO₃ in dioxane atelevated temperatures), wherein if Ring D of compound 10 is substitutedwith an R^(b) substituent that is R^(c)R^(d)N— wherein one or both ofR^(c) and R^(d) is hydrogen, the nitrogen atom of R^(b) may be protectedwith an appropriate amino protecting group prior to coupling. Compound21 may be prepared from compound 19 according to the process describedfor Scheme 3.

Alternatively, when group B is as defined for Formula I other thanhydrogen, compound 23 may be prepared by reacting compound 22 with areagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros,hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substitutedwith a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein thealkyl portion is optionally substituted with a C3-C6 cycloalkylidenering, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3fluoros, (R¹R²N)C1-C6 alkyl-X, hetAr¹C1-C3 alkyl-X, (C3-C6cycloalkyl)C1-C3 alkyl-X, (hetCyc^(a))C1-C3 alkyl-X, hetCyc^(a)-X orhetCyc^(a)C(═O)C1-C6 alkyl-X, where R¹, R², hetAr¹, and hetCyc^(a) areas defined for Formula I and X is a leaving atom or group (such as ahalide or triflate), wherein each of said reagents is optionallysubstituted with a protecting group (e.g., a t-butyldimethylsilyl groupif B has one or two additional hydroxy groups). For example, when B isC1-C6 alkyl optionally substituted with 1-3 fluoros, compound may beprepared by reacting compound 22 with C1-C6 alkyl-X, where X is ahalogen such as Br or Cl, or a leaving group such as triflate. Compound20 may be prepared by coupling compound 23 with compound 10 as describedin Scheme 3. Compound 21 may be prepared from compound 20 according tothe process described for Scheme 3.

Alternatively, when group B is as defined for Formula I other thanhydrogen, compound 20 may be prepared by reacting compound 19 with agroup such as (C1-C6 alkyl)OH, an appropriately substituted (C1-C3alkyl)OH, an appropriately substituted (C1-C6 alkyl)OH, or hetCyc^(a)OH(i.e., where hetCyc^(a) a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and is optionallysubstituted with OH, C1-C6 alkyl (optionally substituted with 1-3fluoros) or hydroxyC1-C6 alkyl) under Mitsunobu reaction conditions(PPh₃ and diisopropyl azodicarboxylate). Compound 21 may be preparedfrom compound 20 according to the process described for Scheme 3.

Scheme 5 shows an alternative general scheme for the synthesis ofCompound 21 where A is H, and B, X¹, X², X³, X⁴, Ring D, R^(a), R^(b),n, m and E are as defined for Formula I.

Compound 22 may be prepared by treating compound 4A (prepared e.g., asdescribed in Scheme 1) with aluminum trichloride.

When group B is as defined for Formula I other than hydrogen, compound23 may be prepared by reacting compound 22 with a reagent such as C1-C6alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-Xwherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portionis optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros,(R¹R²N)C1-C6 alkyl-X, hetAr¹C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3alkyl-X, (hetCyc^(a))C1-C3 alkyl-X, hetCyc^(a)-X or hetCyc^(a)C(═O)C1-C6alkyl-X, where R¹, R², hetAr¹, and hetCyc^(a) are as defined for FormulaI and X is a leaving atom or group (such as a halide or triflate),wherein each of said reagents is optionally substituted with aprotecting group (e.g., a t-butyldimethylsilyl group if B has one or twoadditional hydroxy groups). For example, when B is C1-C6 alkyloptionally substituted with 1-3 fluoros, compound may be prepared byreacting compound 22 with C1-C6 alkyl-X, where X is a halogen such as Bror Cl, or a leaving group such as triflate.

Compound 24 may be prepared by reacting compound 23 with compound 13(where X¹, X², X³ and X⁴ are as defined for Formula I; L² is a leavinggroup such as a triflate or halide); Z is —B(OR^(x))(OR^(y)) and R^(z)and R^(y) are H or (1-6C)alkyl, or R^(x) and R^(y) together with theatoms to which they are connected form a 5-6 membered ring optionallysubstituted with 1-4 substituents selected from (C1-C3 alkyl)) usingappropriate palladium-catalyzed cross-coupling reaction conditions,e.g., Suzuki coupling reaction conditions (for example, a palladiumcatalyst and optionally a ligand in the presence of an inorganic base,for example, Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevated temperatures).

When group B is hydrogen, compound 24 may be prepared by reactingcompound 22 directly with compound 13 as described above.

Compound 20 may be prepared by coupling compound 24 with compound 15where Ring D and E are as defined for Formula I under appropriateS_(N)Ar conditions (for example, optionally in the presence of a basesuch as K₂CO₃ and at elevated temperature). If Ring D of compound 15comprises a substituent having a primary or secondary ring nitrogenatom, the nitrogen atom is protected with an appropriate aminoprotecting group prior to coupling, and then the amino protecting groupmay be removed subsequent to coupling as described above.

Compound 21 may be prepared from compound 20 according to the processdescribed for Scheme 3.

Scheme 6 shows a general scheme for the synthesis of Compound 31 where Ais Cl, and B, X¹, X², X³, X⁴, Ring D, R^(a), R^(b), n, m and E are asdefined for Formula I.

Compound 25 may be prepared by treating compound 4A (prepared e.g., asdescribed in Scheme 1) with aluminum trichloride.

Compound 26 may be prepared by treating compound 25 with aluminumtrichloride.

When group B is as defined for Formula I other than hydrogen, compound27 may be prepared by reacting compound 26 with a reagent such as C1-C6alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-Xwherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portionis optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros,(R¹R²N)C1-C6 alkyl-X, hetAr¹C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3alkyl-X, (hetCyc^(a))C1-C3 alkyl-X, hetCyc^(a)-X or hetCyc^(a)C(═O)C1-C6alkyl-X, where R¹, R², hetAr¹, and hetCyc^(a) are as defined for FormulaI and X is a leaving atom or group (such as a halide or triflate),wherein each of said reagents is optionally substituted with aprotecting group (e.g., a t-butyldimethylsilyl group if B has one or twoadditional hydroxy groups). For example, when B is C1-C6 alkyloptionally substituted with 1-3 fluoros, compound may be prepared byreacting compound 26 with C1-C6 alkyl-X, where X is a halogen such as Bror Cl, or a leaving group such as triflate.

Compounds 28 (when group B is methyl), 29 (when group B is hydrogen) and30 (when group B is other than hydrogen) may be prepared by couplingcompounds 25, 26 and 27, respectively, with the corresponding boronicester compound 10 (where Ring D, E, X¹, X², X³ and X⁴ are as defined forFormula I; Z is —B(OR^(x))(OR^(y)) and R^(z) and R^(y) are H or(1-6C)alkyl, or R^(x) and R^(y) together with the atoms to which theyare connected form a 5-6 membered ring optionally substituted with 1-4substituents selected from (C1-C3 alkyl)) using appropriatepalladium-catalyzed cross-coupling reaction conditions, e.g., Suzukicoupling reaction conditions (for example, a palladium catalyst andoptionally a ligand in the presence of an inorganic base, for example,Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevated temperatures), wherein ifRing D of is substituted with an R^(b) substituent that is R^(c)R^(d)N—wherein one or both of R and R^(d) is hydrogen, the nitrogen atom ofR^(b) may be protected with an appropriate amino protecting group priorto coupling. The amino protecting group if present on a substituent ofRing D of compound 29 or 30 may be removed under standard conditions(for example, a Boc group may be removed by treating compound 1 toacidic conditions, e.g., HCl) to provide compound 31 where E is H.

Alternatively, the E group may be functionalized (i.e., reacted ortreated with an appropriate reagent) under standard conditions such asdescribed below to provide compound 31 where E is as defined for FormulaI except that E is not H.

The E group of compounds 11, 11a, 16, 19, 20, 29 and 30 described inSchemes 1-6 may be functionalized (i.e., reacted or treated with anappropriate reagent) to introduce an E group, where E is any of the Egroups defined for Formula I with the exception of hydrogen, usingstandard chemistry well known to persons skilled in the art. As usedherein, the term “functionalized” refers to a process step in the Egroup of a compound of general Formula I is reacted or treated with anappropriate reagent to provide a compound of Formula I where E is asdefined for Formula I except that E is other than hydrogen.

For example, an amide derivative (e.g., where E is Ar¹C(═O)NR^(g)—,hetAr²C(═O)NR^(g)(CH₂)_(p)— p is 0 or 1, or R⁴R⁵NC(═O)NR^(g)—, may beobtained by reacting compound 11 wherein E is —NH₂ with an carboxylicacid derivative such as an acid chloride using conventional amide bondformation conditions, for example in the presence of a base (e.g., anamine base such as DIEA) in an appropriate solvent (such as DCM) toprovide a functionalized compound 12. Alternative, compound 11 wherein Eis —NH₂ may be reacted with an carboxylic acid using conventional amidebond formation conditions, for example by treating the carboxylic acidwith an activating agent (e.g., HATU) followed by addition of compound11 in the presence of a base ((e.g., an amine base such as DIEA) in anappropriate solvent (such as DMA) to provide a functionalized compound12. The same chemistry may be utilized with compounds 11a, 16, 19, 20,29 and 30 to prepare functionalized compounds 12, 17, 21 and 31.

As another example, a urea derivative, (e.g., where E isR⁴R⁵NHC(═O)NR^(g)—) may be prepared reacting a compound 11 where E is—NH₂ with a compound having the formula R⁴R⁵N═C(═O) where R⁴ and R⁵ areas defined for Formula I in the presence of an appropriate base (e.g.,DIEA) to provide a functionalized compound 12. The same chemistry may beutilized with compounds 11a, 16, 19, 20, 29 and 30 to preparefunctionalized compounds 12, 17, 21 and 31.

As another example, an alkoxy, aryloxy or heteroaryloxy derivative(e.g., where E is (C1-C6 alkoxy)C1-C6 alkoxy, Ar¹O— or hetAr²O—), may beprepared by reacting a compound 11 where E is hydroxy with a compoundhaving the formula (C1-C6 alkoxy)C1-C6 alkyl-X, Ar¹—X or hetAr²—X, whereX is a halogen, in the presence of an inorganic base (e.g., an alkalimetal hydride, such as sodium hydride or potassium hydride) in anappropriate solvent (e.g., an aprotic solvent such as DMA). The samechemistry may be utilized with compounds 11a, 16, 19, 20, 29 and 30 toprepare functionalized compounds 12, 17, 21 and 31.

The term “amino protecting group” as used herein refers to a derivativeof the groups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of suitable protecting groups for use in any of the processesdescribed herein include carbamates, amides, alkyl and aryl groups,imines, as well as many N-heteroatom derivatives which can be removed toregenerate the desired amine group. Non-limiting examples of aminoprotecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl(“Boc”), benzyloxycarbonyl (“CBz”) and 9-fluorenylmethyleneoxycarbonyl(“Fmoc”). Further examples of these groups, and other protecting groups,are found in T. W. Greene, et al. Greene's Protective Groups in OrganicSynthesis. New York: Wiley Interscience, 2006.

Accordingly, further provided herein is a process for preparing of acompound of Formula I or a pharmaceutically acceptable salt thereof asdefined herein which comprises:

(a) for a compound of Formula I where E is H, A is CN, and B, X¹, X²,X³, X⁴, Ring D, R^(a), R^(b), m and n are as defined for Formula I,coupling a corresponding compound 9 having the formula

where B is as defined for Formula I, with a corresponding boronate esterhaving the formula 10

where Z is —B(OR^(x))(OR^(y)) and R^(x) and R^(y) are H or (1-6C)alkyl,or R^(x) and R^(y) together with the atoms to which they are connectedform a 5-6 membered ring optionally substituted with 1-4 substituentsselected from (C1-C3 alkyl), and Ring D, E, X¹, X², X³, X⁴, R^(a),R^(b), m and n are as defined for Formula I, wherein if Ring D issubstituted with an R^(b) substituent that is R^(c)R^(d)N— wherein oneor both of R^(c) and R^(d) is hydrogen, the nitrogen atom of R^(b) maybe protected with an amino protecting group prior to coupling, in thepresence of a palladium catalyst and optionally a ligand and in thepresence of a base, optionally followed by removal of the aminoprotecting group if present; or

(b) for a compound of Formula I where A, B, X¹, X², X³, X⁴, Ring D,R^(a), R^(b), m, n, and E are as defined for Formula I with theexception that E is not hydrogen, functionalizing a correspondingcompound of the formula

wherein Ring D, B, X¹, X², X³, X⁴, R^(a), R^(b), m and n are as definedfor Formula I and E¹ is —NH₂ or OH; or

(c) for a compound of Formula I where A is CN and B, X¹, X², X³, X⁴,Ring D, R^(a), R^(b), m, n, and E are as defined for Formula I, reactinga corresponding compound of the formula

wherein Ring D, B, X¹, X², X³, and X⁴ are as defined for Formula I andL² is a leaving group such as a halogen or triflate, with a compound ofthe formula 15

wherein Ring D, R^(a), R^(b), m, n, and E are as defined for Formula Iand wherein if Ring D is substituted with an R^(b) substituent that isR^(c)R^(d)N— wherein one or both of R and R^(d) is hydrogen, thenitrogen atom of R^(b) may be protected with an appropriate aminoprotecting group prior to coupling, in the presence of a base,optionally followed by removal of the amino protecting group if present;or

(d) for a compound of Formula I where E is H, A is CN, and B, X¹, X²,X³, X⁴, and Ring D are as defined for Formula I, coupling acorresponding compound of formula 14

where L² is a leaving group and B, X¹, X², X³, and X⁴ are as defined forFormula I, with a compound of formula 15

where Ring D, R^(a), R^(b), m and n are as defined for Formula I and Eis hydrogen, wherein if Ring D is substituted with an R^(b) substituentthat is R^(c)R^(d)N— wherein one or both of R^(c) and R^(d) is hydrogen,the nitrogen atom of R^(b) may be protected with an appropriate aminoprotecting group prior to coupling, in the presence of a base,optionally followed by removal of the amino protecting group if present;or

(e) for a compound of Formula I where A is H, B is H, and X¹, X², X³,X⁴, Ring D and E are as defined for Formula I, treating a correspondingcompound of formula 18

where A is H, B is H, and X¹, X², X³, X⁴, Ring D, R^(a), R^(b), m, n,and E are as defined for Formula I wherein if Ring D is substituted withan R^(b) substituent that is R^(c)R^(d)N— wherein one or both of R^(c)and R^(d) is hydrogen, the nitrogen atom of R^(b) may be protected withan amino protecting group, with aluminum trichloride to provide compound19

optionally followed by removal of the amino protecting group if present;or

(f) for a compound of Formula I where A is H, and B, X¹, X², X³, X⁴,Ring D, R^(a), R^(b), m, n, and E are as defined for Formula I,

-   -   (i) treating a corresponding compound of formula 18

where A is H, and X¹, X², X³, X⁴, Ring D, R^(a), R^(b), m, n, and E areas defined for Formula I, wherein if Ring D is substituted with an R^(b)substituent that is R^(c)R^(d)N— wherein one or both of R and R^(d) ishydrogen, the nitrogen atom of R^(b) may be protected with anappropriate amino protecting group, with aluminum trichloride to providecompound 19

-   -   (ii) reacting compound 19 with C1-C6 alkyl-X optionally        substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the        alkyl portion is optionally substituted with a C3-C6        cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl        portion is optionally substituted with a C3-C6 cycloalkylidene        ring, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with        1-3 fluoros, (R¹R²N)C1-C6 alkyl-X, hetAr¹C1-C3 alkyl-X, (C3-C6        cycloalkyl)C1-C3 alkyl-X, (hetCyc^(a))C1-C3 alkyl-X,        hetCyc^(a)-X or hetCyc^(a)C(═O)C1-C6 alkyl-X, where R¹, R²,        hetAr¹, and hetCyc^(a) are as defined for Formula I and X is a        leaving atom or group, optionally followed by removal of the        amino protecting group if present; or

(g) for a compound of Formula I where A is H or Cl, B is H, and X¹, X²,X³, X⁴, Ring D, R^(a), R^(b), m, n, and E are as defined for Formula I,coupling a compound of formula

where A is H or C1 with a boronate ester having formula 10

where Z is —B(OR^(x))(OR^(y)) and R^(x) and R^(y) are H or (1-6C)alkyl,or R^(x) and R^(y) together with the atoms to which they are connectedform a 5-6 membered ring optionally substituted with 1-4 substituentsselected from (C1-C3 alkyl), and Ring D, E, X¹, X², X³, X⁴, R^(a),R^(b), m and n are as defined for Formula I, wherein if Ring D issubstituted with an R^(b) substituent that is R^(c)R^(d)N— wherein oneor both of R^(c) and R^(d) is hydrogen, the nitrogen atom of R^(b) maybe protected with an amino protecting group prior to said coupling, inthe presence of a palladium catalyst and optionally a ligand and in thepresence of a base, optionally followed by removal of the aminoprotecting group if present; or

(h) for a compound of Formula I where A is H or Cl, and B, X¹, X², X³,X⁴, Ring D, R^(a), R^(b), m, n, and E are as defined for Formula I,coupling a compound of the formula

where A is H or Cl, with a corresponding boronate ester compound offormula 10

where Z is —B(OR^(x))(OR^(y)) and R^(x) and R^(y) are H or (1-6C)alkyl,or R^(x) and R^(y) together with the atoms to which they are connectedform a 5-6 membered ring optionally substituted with 1-4 substituentsselected from (C1-C3 alkyl), and Ring D, E, X¹, X², X³, X⁴, R^(a),R^(b), m and n are as defined for Formula I, wherein if Ring D issubstituted with an R^(b) substituent that is R^(c)R^(d)N— wherein oneor both of R^(c) and R^(d) is hydrogen, the nitrogen atom of R^(b) maybe protected with an amino protecting group prior to said coupling, inthe presence of a palladium catalyst and optionally a ligand and in thepresence of a base, and optionally followed by removal of the aminoprotecting group if present; or

(i) for a compound of Formula I where A is H, and B, X¹, X², X³, X⁴,Ring D, R^(a), R^(b), m, n, and E are as defined for Formula I, couplinga compound of formula 24

where B, X¹, X², X³ and X⁴, are as defined for Formula I and L² is aleaving group or atom, with a corresponding compound of formula 15

where Ring D, R^(a), R^(b), m, n, and E are as defined for Formula Iwherein if Ring D is substituted with an R^(b) substituent that isR^(c)R^(d)N— wherein one or both of R and R^(d) is hydrogen, thenitrogen atom of R^(b) may be protected with an amino protecting group,optionally followed by removal of the amino protecting group if present;and

removing any additional protecting groups if present and optionallyforming a pharmaceutically acceptable salt thereof.

The term “amino protecting group” as used herein refers to a derivativeof the groups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of suitable protecting groups for use in any of the processesdescribed herein include carbamates, amides, alkyl and aryl groups,imines, as well as many N-heteroatom derivatives which can be removed toregenerate the desired amine group. Non-limiting examples of aminoprotecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl(“Boc”), benzyloxycarbonyl (“CBz”) and 9-fluorenylmethyleneoxycarbonyl(“Fmoc”). Further examples of these groups, and other protecting groups,are found in T. W. Greene, et al., Greene's Protective Groups in OrganicSynthesis. New York: Wiley Interscience, 2006.

Hydroxy groups may be protected with any convenient hydroxy protectinggroup, for example as described in T. W. Greene, et al., Greene'sProtective Groups in Organic Synthesis. New York: Wiley Interscience,2006. Examples include benzyl, trityl, silyl ethers, and the like.

Nitrogen atoms in compounds described in any of the above methods may beprotected with any convenient nitrogen protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof nitrogen protecting groups include acyl and alkoxycarbonyl groups,such as t-butoxycarbonyl (BOC), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).

The ability of test compounds to act as RET inhibitors may bedemonstrated by the assay described in Example A. IC₅₀ values are shownin Table 5.

In some embodiments, the compounds provided herein exhibit potent andselective RET inhibition. For example, the compounds provided hereinexhibit nanomolar potency against wild type RET and select RET mutants,including the KIF5B-RET fusion and V804M gatekeeper mutation, withminimal activity against related kinases.

In some embodiments, the compounds of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, selectively target a RET kinase. Forexample, a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof, can selectively target a RET kinase over anotherkinase or non-kinase target.

In some embodiments, a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, exhibits at least a 30-foldselectivity for a RET kinase over another kinase. For example, acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, exhibits at least a 40-fold selectivity; at least a 50-foldselectivity; at least a 60-fold selectivity; at least a 70-foldselectivity; at least a 80-fold selectivity; at least a 90-foldselectivity; at least 100-fold selectivity; at least 200-foldselectivity; at least 300-fold selectivity; at least 400-foldselectivity; at least 500-fold selectivity; at least 600-foldselectivity; at least 700-fold selectivity; at least 800-foldselectivity; at least 900-fold selectivity; or at least 1000-foldselectivity for a RET kinase over another kinase. In some embodiments,selectivity for a RET kinase over another kinase is measured in acellular assay (e.g., a cellular assay as provided herein).

In some embodiments, the compounds provided herein can exhibitselectivity for a RET kinase over a KDR kinase (e.g., VEGFR2). In someembodiments, the selectivity for a RET kinase over a KDR kinase isobserved without loss of gatekeeper mutant potency. In some embodiments,the selectivity over a KDR kinase is at least 10-fold (e.g., at least a40-fold selectivity; at least a 50-fold selectivity; at least a 60-foldselectivity; at least a 70-fold selectivity; at least a 80-foldselectivity; at least a 90-fold selectivity; at least 100-foldselectivity; at least 150-fold selectivity; at least 200-foldselectivity; at least 250-fold selectivity; at least 300-foldselectivity; at least 350-fold selectivity; or at least 400-foldselectivity) as compared to the inhibition of KIF5B-RET (i.e. thecompounds were more potent against KIF5B-RET than KDR). In someembodiments, the selectivity for a RET kinase over a KDR kinase is about30-fold. In some embodiments, the selectivity for a RET kinase over aKDR kinase is at least 100-fold. In some embodiments, the selectivityfor a RET kinase over a KDR kinase is at least 150-fold. In someembodiments, the selectivity for a RET kinase over a KDR kinase is atleast 400-fold. Without being bound by any theory, potent KDR kinaseinhibition is believed to be a common feature among multikinaseinhibitors (MKIs) that target RET and may be the source of thedose-limiting toxicities observed with such compounds.

In some embodiments, inhibition of V804M was similar to that observedfor wild-type RET. For example, inhibition of V804M was within about2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of inhibitionof wild-type RET (i.e. the compounds were similarly potent againstwild-type RET and V804M). In some embodiments, selectivity for awildtype or V804M RET kinase over another kinase is measured in anenzyme assay (e.g., an enzyme assay as provided herein). In someembodiments, the compounds provided herein exhibit selectivecytotoxicity to RET-mutant cells.

In some embodiments, the compounds provided herein exhibit brain and/orcentral nervous system (CNS) penetrance. Such compounds are capable ofcrossing the blood brain barrier and inhibiting a RET kinase in thebrain and/or other CNS structures. In some embodiments, the compoundsprovided herein are capable of crossing the blood brain barrier in atherapeutically effective amount. For example, treatment of a patientwith cancer (e.g., a RET-associated cancer such as a RET-associatedbrain or CNS cancer) can include administration (e.g., oraladministration) of the compound to the patient. In some suchembodiments, the compounds provided herein are useful for treating aprimary brain tumor or metastatic brain tumor.

In some embodiments, the compounds of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, exhibit one or more of high GIabsorption, low clearance, and low potential for drug-drug interactions.

Compounds of Formula I are useful for treating diseases and disorderswhich can be treated with a RET kinase inhibitor, such as RET-associateddiseases and disorders, e.g., proliferative disorders such as cancers,including hematological cancers and solid tumors, and gastrointestinaldisorders such as IBS.

As used herein, terms “treat” or “treatment” refer to therapeutic orpalliative measures. Beneficial or desired clinical results include, butare not limited to, alleviation, in whole or in part, of symptomsassociated with a disease or disorder or condition, diminishment of theextent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state (e.g., one or more symptoms of the disease), andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment.

As used herein, the terms “subject,” “individual,” or “patient,” areused interchangeably, refers to any animal, including mammals such asmice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, primates, and humans. In some embodiments, the patient is ahuman. In some embodiments, the subject has experienced and/or exhibitedat least one symptom of the disease or disorder to be treated and/orprevented. In some embodiments, the subject has been identified ordiagnosed as having a cancer with a dysregulation of a RET gene, a RETprotein, or expression or activity, or level of any of the same (aRET-associated cancer) (e.g., as determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit). In some embodiments,the subject has a tumor that is positive for a dysregulation of a RETgene, a RET protein, or expression or activity, or level of any of thesame (e.g., as determined using a regulatory agency-approved assay orkit). The subject can be a subject with a tumor(s) that is positive fora dysregulation of a RET gene, a RET protein, or expression or activity,or level of any of the same (e.g., identified as positive using aregulatory agency-approved, e.g., FDA-approved, assay or kit). Thesubject can be a subject whose tumors have a dysregulation of a RETgene, a RET protein, or expression or activity, or a level of the same(e.g., where the tumor is identified as such using a regulatoryagency-approved, e.g., FDA-approved, kit or assay). In some embodiments,the subject is suspected of having a RET-associated cancer. In someembodiments, the subject has a clinical record indicating that thesubject has a tumor that has a dysregulation of a RET gene, a RETprotein, or expression or activity, or level of any of the same (andoptionally the clinical record indicates that the subject should betreated with any of the compositions provided herein). In someembodiments, the patient is a pediatric patient.

The term “pediatric patient” as used herein refers to a patient underthe age of 21 years at the time of diagnosis or treatment. The term“pediatric” can be further be divided into various subpopulationsincluding: neonates (from birth through the first month of life);infants (1 month up to two years of age); children (two years of age upto 12 years of age); and adolescents (12 years of age through 21 yearsof age (up to, but not including, the twenty-second birthday)). BerhmanR E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics,15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph A M, et al.Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins;1994. In some embodiments, a pediatric patient is from birth through thefirst 28 days of life, from 29 days of age to less than two years ofage, from two years of age to less than 12 years of age, or 12 years ofage through 21 years of age (up to, but not including, the twenty-secondbirthday). In some embodiments, a pediatric patient is from birththrough the first 28 days of life, from 29 days of age to less than 1year of age, from one month of age to less than four months of age, fromthree months of age to less than seven months of age, from six months ofage to less than 1 year of age, from 1 year of age to less than 2 yearsof age, from 2 years of age to less than 3 years of age, from 2 years ofage to less than seven years of age, from 3 years of age to less than 5years of age, from 5 years of age to less than 10 years of age, from 6years of age to less than 13 years of age, from 10 years of age to lessthan 15 years of age, or from 15 years of age to less than 22 years ofage.

In certain embodiments, compounds of Formula I are useful for preventingdiseases and disorders as defined herein (for example, autoimmunediseases, inflammatory diseases, and cancer). The term “preventing” asused herein means the prevention of the onset, recurrence or spread, inwhole or in part, of the disease or condition as described herein, or asymptom thereof.

The term “RET-associated disease or disorder” as used herein refers todiseases or disorders associated with or having a dysregulation of a RETgene, a RET kinase (also called herein RET kinase protein), or theexpression or activity or level of any (e.g., one or more) of the same(e.g., any of the types of dysregulation of a RET gene, a RET kinase, aRET kinase domain, or the expression or activity or level of any of thesame described herein). Non-limiting examples of a RET-associateddisease or disorder include, for example, cancer and gastrointestinaldisorders such as irritable bowel syndrome (IBS).

The term “RET-associated cancer” as used herein refers to cancersassociated with or having a dysregulation of a RET gene, a RET kinase(also called herein RET kinase protein), or expression or activity, orlevel of any of the same. Non-limiting examples of a RET-associatedcancer are described herein.

The phrase “dysregulation of a RET gene, a RET kinase, or the expressionor activity or level of any of the same” refers to a genetic mutation(e.g., a RET gene translocation that results in the expression of afusion protein, a deletion in a RET gene that results in the expressionof a RET protein that includes a deletion of at least one amino acid ascompared to the wild-type RET protein, a mutation in a RET gene thatresults in the expression of a RET protein with one or more pointmutations, or an alternative spliced version of a RET mRNA that resultsin a RET protein having a deletion of at least one amino acid in the RETprotein as compared to the wild-type RET protein) or a RET geneamplification that results in overexpression of a RET protein or anautocrine activity resulting from the overexpression of a RET gene in acell that results in a pathogenic increase in the activity of a kinasedomain of a RET protein (e.g., a constitutively active kinase domain ofa RET protein) in a cell. As another example, a dysregulation of a RETgene, a RET protein, or expression or activity, or level of any of thesame, can be a mutation in a RET gene that encodes a RET protein that isconstitutively active or has increased activity as compared to a proteinencoded by a RET gene that does not include the mutation. For example, adysregulation of a RET gene, a RET protein, or expression or activity,or level of any of the same, can be the result of a gene or chromosometranslocation which results in the expression of a fusion protein thatcontains a first portion of RET that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notRET). In some examples, dysregulation of a RET gene, a RET protein, orexpression or activity or level of any of the same can be a result of agene translocation of one RET gene with another non-RET gene.Non-limiting examples of fusion proteins are described in Table 1.Non-limiting examples of RET kinase protein pointmutations/insertions/deletions are described in Table 2. Additionalexamples of RET kinase protein mutations (e.g., point mutations) are RETinhibitor resistance mutations. Non-limiting examples of RET inhibitorresistance mutations are described in Tables 3 and 4.

The term “wildtype” or “wild-type” describes a nucleic acid (e.g., a RETgene or a RET mRNA) or protein (e.g., a RET protein) that is found in asubject that does not have a RET-associated disease, e.g., aRET-associated cancer (and optionally also does not have an increasedrisk of developing a RET-associated disease and/or is not suspected ofhaving a RET-associated disease), or is found in a cell or tissue from asubject that does not have a RET-associated disease, e.g., aRET-associated cancer (and optionally also does not have an increasedrisk of developing a RET-associated disease and/or is not suspected ofhaving a RET-associated disease).

The term “regulatory agency” refers to a country's agency for theapproval of the medical use of pharmaceutical agents with the country.For example, a non-limiting example of a regulatory agency is the U.S.Food and Drug Administration (FDA).

Provided herein is a method of treating cancer (e.g., a RET-associatedcancer) in a patient in need of such treatment, the method comprisingadministering to the patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof or a pharmaceutical composition thereof. For example, providedherein are methods for treating a RET-associated cancer in a patient inneed of such treatment, the method comprising a) detecting adysregulation of a RET gene, a RET kinase, or the expression or activityor level of any of the same in a sample from the patient; and b)administering a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the dysregulation of a RET gene, a RET kinase, or theexpression or activity or level of any of the same includes one or morefusion proteins. Non-limiting examples of RET gene fusion proteins aredescribed in Table 1. In some embodiments, the fusion protein isKIF5B-RET. In some embodiments, the dysregulation of a RET gene, a RETkinase, or the expression or activity or level of any of the sameincludes one or more RET kinase protein point mutations/insertions.Non-limiting examples of RET kinase protein pointmutations/insertions/deletions are described in Table 2. In someembodiments, the RET kinase protein point mutations/insertions/deletionsare selected from the group consisting of M918T, M918V, C634W, V804L,and V804M. In some embodiments, a compound of Formula I is selectedfromi) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-49;iv) Example No. 50-70; v) Example No. 71-89; vi) Example No. 90-109;vii) Example No. 110-129; viii) Example No. 130-149; ix) Example No.150-169; x) Example No. 170-189; xi) Example No. 190-209; xii) ExampleNo. 210-229; xiii) Example No. 230-249; xiv) Example No. 250-259; xv)Example No. 270-289; xvi) Example No. 290-309; xvii) Example No.310-329; xviii) Example No. 330-349; xix) Example No. 350-369; xx)Example No. 370-384; xxi) Example No. 385-394; xxii) Example No.395-407; xxiii) Example No. 408-427; xxiii) Example No. 428-447; xxiv)Example No. 448-467; or xxvi) Example No. 468-488; xxvii) Example No.489-509; xxviii) Example No. 510-530; xxvix) Example No. 531-551; xxx)Example No. 552-572; xxxi) Example No. 573-593; xxxii) Example No.594-614; xxxiii) Example No. 615-635; xxxiv) Example No. 636-686; xxxv)Example No. 687-707; xxxvi) Example No. 708-728; xxxvii) Example No.729-749; xxxviii) Example No. 750-770; xxxix) Example No. 771-791; xl)Example No. 792-812; xli) Example No. 813-819.

In some embodiments of any of the methods or uses described herein, thecancer (e.g., RET-associated cancer) is a hematological cancer. In someembodiments of any of the methods or uses described herein, the cancer(e.g., RET-associated cancer) is a solid tumor. In some embodiments ofany of the methods or uses described herein, the cancer (e.g.,RET-associated cancer) is lung cancer (e.g., small cell lung carcinomaor non-small cell lung carcinoma), papillary thyroid cancer, medullarythyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer,refractory differentiated thyroid cancer, lung adenocarcinoma,bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroidhyperplasia, breast cancer, colorectal cancer (e.g., metastaticcolorectal cancer), papillary renal cell carcinoma, ganglioneuromatosisof the gastroenteric mucosa, inflammatory myofibroblastic tumor, orcervical cancer. In some embodiments of any of the methods or usesdescribed herein, the cancer (e.g., RET-associated cancer) is selectedfrom the group of: acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), cancer in adolescents, adrenocortical carcinoma, analcancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor,basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer,brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkittlymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumors,cervical cancer, childhood cancers, chordoma, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyeloproliferative neoplasms, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductalcarcinoma in situ, embryonal tumors, endometrial cancer, ependymoma,esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranialgerm cell tumor, extragonadal germ cell tumor, extrahepatic bile ductcancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone,gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia,head and neck cancer, heart cancer, hepatocellular cancer,histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocularmelanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposisarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer,leukemia, lip and oral cavity cancer, liver cancer, lung cancer,lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone,osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma,metastatic squamous neck cancer, midline tract carcinoma, mouth cancer,multiple endocrine neoplasia syndromes, multiple myeloma, mycosisfungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferativeneoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma,myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-smallcell lung cancer, oral cancer, oral cavity cancer, lip cancer,oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer,papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma,pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma,pregnancy and breast cancer, primary central nervous system lymphoma,primary peritoneal cancer, prostate cancer, rectal cancer, renal cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer,sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamousneck cancer, stomach cancer, T-cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, unknown primary carcinoma,urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, and Wilms' tumor.

In some embodiments, a hematological cancer (e.g., hematological cancersthat are RET-associated cancers) is selected from the group consistingof leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease(also called Hodgkin's lymphoma), and myeloma, for instance, acutelymphocytic leukemia (ALL), acute myeloid leukemia (AML), acutepromyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML),chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia(AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia(PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AMLwith trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL),myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD),and multiple myeloma (MM). Additional examples of hematological cancersinclude myeloproliferative disorders (MPD) such as polycythemia vera(PV), essential thrombocytopenia (ET) and idiopathic primarymyelofibrosis (IMF/IPF/PMF). In one embodiment, the hematological cancer(e.g., the hematological cancer that is a RET-associated cancer) is AMLor CMML.

In some embodiments, the cancer (e.g., the RET-associated cancer) is asolid tumor. Examples of solid tumors (e.g., solid tumors that areRET-associated cancers) include, for example, thyroid cancer (e.g.,papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer(e.g., lung adenocarcinoma, small-cell lung carcinoma), pancreaticcancer, pancreatic ductal carcinoma, breast cancer, colon cancer,colorectal cancer, prostate cancer, renal cell carcinoma, head and necktumors, neuroblastoma, and melanoma. See, for example, Nature ReviewsCancer, 2014, 14, 173-186.

In some embodiments, the cancer is selected from the group consisting oflung cancer, papillary thyroid cancer, medullary thyroid cancer,differentiated thyroid cancer, recurrent thyroid cancer, refractorydifferentiated thyroid cancer, multiple endocrine neoplasia type 2A or2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroidhyperplasia, breast cancer, colorectal cancer, papillary renal cellcarcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervicalcancer.

In some embodiments, the patient is a human.

Compounds of Formula I and pharmaceutically acceptable salts andsolvates thereof are also useful for treating a RET-associated cancer.

Accordingly, also provided herein is a method for treating a patientdiagnosed with or identified as having a RET-associated cancer, e.g.,any of the exemplary RET-associated cancers disclosed herein, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof as defined herein.

Dysregulation of a RET kinase, a RET gene, or the expression or activityor level of any (e.g., one or more) of the same can contribute totumorigenesis. For example, a dysregulation of a RET kinase, a RET gene,or expression or activity or level of any of the same can be atranslocation, overexpression, activation, amplification, or mutation ofa RET kinase, a RET gene, or a RET kinase domain. Translocation caninclude translocations involving the RET kinase domain, mutations caninclude mutations involving the RET ligand-binding site, andamplification can be of a RET gene. Other dysregulations can include RETmRNA splice variants and RET autocrine/paracrine signaling, which canalso contribute to tumorigenesis.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includesoverexpression of wild-type RET kinase (e.g., leading to autocrineactivation). In some embodiments, the dysregulation of a RET gene, a RETkinase protein, or expression or activity or level of any of the same,includes overexpression, activation, amplification, or mutation in achromosomal segment comprising the RET gene or a portion thereof,including, for example, the kinase domain portion, or a portion capableof exhibiting kinase activity.

In some embodiments, the dysregulation of a RET gene, a RET kinaseprotein, or expression or activity or level of any of the same, includesone or more chromosome translocations or inversions resulting in a RETgene fusion. In some embodiments, the dysregulation of a RET gene, a RETkinase protein, or expression or activity or level of any of the same,is a result of genetic translocations in which the expressed protein isa fusion protein containing residues from a non-RET partner protein, andincludes a minimum of a functional RET kinase domain.

Non-limiting examples of RET fusion proteins are shown in Table 1.

TABLE 1 Exemplary RET Fusion Partners and Cancers Non-limiting ExemplaryFusion Partner RET-Associated Cancer(s) BCR Chronic MyelomonocyticLeukemia (CMML) CLIP1 Adenocarcinoma KIF5B NSCLC, Ovarian Cancer,Spitzoid Neoplasms; Lung Adenocarcinoma^(3,4,14,28); AdenosquamousCarcinomas¹⁵ CCDC6 (also called PTC1, NSCLC, Colon Cancer, D10S170, orH4) Papillary Thyroid Cancer; Adenocarcinomas; Lung Adenocarcinoma;Metastatic Colorectal Cancer⁵; Adenosquamous Carcinomas¹⁵, BreastCancer³⁰ PTC1ex9 (a novel CCDC6 Metastatic papillary thyroidrearrangement) cancer² NCOA4 (also called PTC3, Papillary ThyroidCancer²¹, ELE1, and RFG) NSCLC, Colon Cancer, Salivary Gland Cancer,Metastatic Colorectal Cancer⁵; Lung Adenocarcinoma¹⁵; AdenosquamousCarcinomas¹⁵ Diffuse Sclerosing Variant of Papillary Thyroid Cancer¹⁶,Breast Cancer³⁰, Acinic Cell Carcinoma³², Mammary Analog SecretoryCarcinoma³³ TRIM33 (also called PTC7, NSCLC, Papillary Thyroid RFG7)Cancer ERC1 (also called ELKS) Papillary Thyroid Cancer, Breast CancerFGFR1OP CMML, Primary Myelofibrosis with secondary Acute MyeloidLeukemia MBD1(also known as PCM1) Papillary Thyroid Cancer RAB61P2Papillary Thyroid Cancer PRKAR1A (also called PTC2) Papillary ThyroidCancer TRIM24 (also called PTC6) Papillary Thyroid Cancer KTN1 (alsocalled PTC8) Papillary Thyroid Cancer GOLGA5 (also called PTC5)Papillary Thyroid Cancer, Spitzoid Neoplasms HOOK3 Papillary ThyroidCancer KIAA1468 (also called PTC9 and Papillary Thyroid Cancer, RFG9)Lung Adenocarcinoma^(8,12) TRIM27 (also called RFP) Papillary ThyroidCancer AKAP13 Papillary Thyroid Cancer FKBP15 Papillary Thyroid CancerSPECC1L Papillary Thyroid Cancer; Thyroid Gland Carcinoma TBL1XR1Papillary Thyroid Cancer; Thyroid Gland Carcinoma CEP55 Diffuse GastricCancer⁷ CUX1 Lung Adenocarcinoma ACBD5 Papillary Thyroid Carcinoma MYH13Medullary Thyroid Carcinoma¹ Uncharacterized InflammatoryMyofibroblastic Tumor⁶ PIBF1 Bronchiolus Lung Cell Carcinoma⁹ KIAA1217(also called SKT) Papillary Thyroid Cancer^(10,13) Lung Adenocarcinoma¹⁴NSCLC¹⁴ MPRIP NSCLC¹¹ HRH4-RET Thyroid cancer and/or paillary thyroidcarcinoma¹⁷ Ria-RET Thyroid cancer and/or papillary thyroid carcinoma¹⁷RFG8 Papillary thyroid carcinoma¹⁸ FOXP4 Lung adenocarcinoma¹⁹ MYH10Infantile myofibromatosis²⁰ HTIF1 Various²² H4L Various²² PTC4 (a novelNCO4/ELE1 Papillary thyroid cancer²³ rearrangement) FRMD4A NSCLC²⁴SQSTM1 Papillary thyroid carcinoma²⁵ AFAP1L2 Papillary thyroidcarcinoma²⁵ AFAP1 NSCLC³¹ PPFIBP2 Papillary thyroid carcinoma²⁵ EML4papillary thyroid cancer²⁶ PARD3 NSCLC²⁷ UVELD Papillary thyroidcancer²⁹ RASGEF1A Breast cancer³⁰ TEL In vitro³⁴ RUFY1 ColorectalCancer³⁵ OLFM4 Small-Bowel Cancer³⁶ UEVLD Papillary Thyroid Carcinoma³⁷DLG5 Non-Anaplastic Thyroid (NAT) Cancer³⁸ RRBP1 Colon Cancer³⁹ ¹Grubbset al., J. Clin. Endocrinol. Metab. 100: 788-793, 2015. ²Halkova et al.,Human Pathology 46: 1962-1969, 2015. ³U.S. Pat. No. 9,297,011 ⁴U.S. Pat.No. 9,216,172 ⁵Le Rolle et al., Oncotarget. 6(30): 28929-37, 2015.⁶Antonescu et al., Am J Surg Pathol. 39(7): 957-67, 2015. ⁷U.S. patentapplication Pub. No. 2015/0177246. ⁸U.S. patent application Pub. No.2015/0057335. ⁹Japanese Patent Application Publication No. 2015/109806A.¹⁰Chinese Patent Application Publication No. 105255927A. ¹¹Fang, et al.Journal of Thoracic Oncology 11.2 (2016): S21-S22. ¹²European PatentApplication Publication No. EP3037547A1. ¹³Lee et al., Oncotarget. DOI:10.18632/oncotarget.9137, e-published ahead of printing, 2016. ¹⁴Saitoet al., Cancer Science 107: 713-720, 2016. ¹⁵Pirker et al., Transl. LungCancer Res. 4(6): 797-800, 2015. ¹⁶Joung et al., Histopathology 69(1):45-53, 2016. ¹⁷PCT patent application Pub. No. WO 2016/141169.¹⁸Klugbauer et al., Cancer Res., 60(24): 7028-32, 2000. ¹⁹Bastien etal., Journal of Molecular Diagnostics, 18(6): 1027, Abstract Number:S120, 2016 Annual Meeting of the Association for Molecular Pathology,Charlotte, NC, 2016. ²⁰Rosenzweig et al., Pediatr Blood Cancer, doi:10.1002/pbc.26377, 2016. ²¹Su et al., PLoS One, 11(111): e0165596, 2016.²²U.S. Pat. No. 9,487,491. ²³Fugazzola et al., Oncogene, 13(5): 1093-7,1996. ²⁴Velcheti et al., J Thorac Oncol., 12(2): e15-e16. doi:10.1016/j.jtho.2016.11.274, 2017. ²⁵Iyama et al., Thyroid, doi:10.1089/thy.2016.0673, 2017. ²⁶Demeure et al., World J Surg.. 38(6):1296-305. doi: 10.1007/s00268-014-2485-3, 2014. ²⁷Sabari et al.,Oncoscience, Advance Publications,www.impactjournals.com/oncoscience/files/papers/1/345/345.pdf, 2017.²⁸U.S. patent application Pub. No. 2017/0014413. ²⁹Lu et al.,Oncotarget, doi: 10.18632/oncotarget.17412, [Epub ahead of print], 2017.³⁰Hirshfield et al., Cancer Research, (February 2017) Vol. 77, No. 4,Supp. 1. Abstract Number: P3-07-02. Meeting Info: 39th Annual CTRC-AACRSan Antonio Breast Cancer Symposium. San Antonio, TX, United States. 6Dec. 2016-10 Dec. 2016. ³¹Morgensztern et al., Journal of ThoracicOncology, (January 2017) Vol. 12, No. 1, Supp. 1, pp. S717-S718,Abstract Number: P1.07-035, Meeting Info: 17th World Conference of theInternational Association for the Study of Lung Cancer, IASLC 2016.Vienna, Austria. 4 Dec. 2016. ³²Dogan et al., Laboratory Investigation,(February 2017) Vol. 97, Supp. 1, pp. 323A. Abstract Number: 1298,Meeting Info: 106th Annual Meeting of the United States and CanadianAcademy of Pathology, USCAP 2017. San Antonio, TX, United States.³³Dogan et al., MODERN PATHOLOGY, Vol. 30, Supp. [2], pp. 323A-323A. MA1298, 2017. ³⁴PCT Patent Application Publication No. WO 2017/146116.³⁵PCT patent application Publication No. WO 2017/122815. ³⁶Reeser etal., J. Mol. Diagn., 19(5): 682-696, doi: 10.1016/j.jmoldx.2017.05.006,2017. ³⁷Lu et al., Oncotarget, 8(28): 45784-45792, doi:10.18632/oncotarget.17412, 2017. ³⁸Ibrahimpasic et al., Clin. CancerRes., doi: 10.1158/1078-0432.CCR-17-1183, 2017 ³⁹Kloosterman et al.,Cancer Res., 77(14): 3814-3822. doi: 10.1158/0008-5472.CAN-16-3563,2017.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes one or moredeletions (e.g., deletion of an amino acid at position 4), insertions,or point mutation(s) in a RET kinase. In some embodiments, thedysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, includes a deletion of one or more residuesfrom the RET kinase, resulting in constitutive activity of the RETkinase domain.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a RET gene that results in the production of a RETkinase that has one or more amino acid substitutions, insertions, ordeletions as compared to the wild-type RET kinase (see, for example, thepoint mutations listed in Table 2).

TABLE 2 Activating RET Kinase Protein PointMutations/Insertions/Deletions Exemplary RET Point Mutations Amino acidposition 2 Amino acid position 3 Amino acid position 4 Amino acidposition 5 Amino acid position 6 Amino acid position 7 Amino acidposition 8 Amino acid position 11 Amino acid position 12 Amino acidposition 13 Amino acid position 20 Amino acid position 32 (e.g., S32L)Amino acid position 34 (e.g., D34S) Amino acid position 40 (e.g., L40P)Amino acid position 56 (e.g., L56M)³⁰ Amino acid position 64 (e.g.,P64L) Amino acid position 67 (e.g., R67H) Amino acid position 114 (e.g.,R114H) Amino acid position 136 (e.g., glutamic acid to stop codon) Aminoacid position 145 (e.g., V145G) Amino acid position 180 (e.g., arginineto stop codon) Amino acid position 200 Amino acid position 292 (e.g.,V292M) Amino acid position 294 Amino acid position 321 (e.g., G321R)Amino acid position 330 (e.g., R330Q) Amino acid position 338 (e.g.,T338I) Amino acid position 360 (e.g., R360W) Amino acid position 373(e.g., alanine to frameshift) Amino acid position 393 (e.g., F393L)Amino acid position 423 (e.g., G423R)²⁷ Amino acid position 432 Aminoacid position 446 (e.g., G446R)²⁸ Δ Amino acid positions 505-506 (6-BasePair In-Frame Germline Deletion in Exon 7)³ Amino acid position 510(e.g., A510V) Amino acid position 511 (e.g., E511K) Amino acid position513 (e.g., G513D)⁷* Amino acid position 515 (e.g., C515S, C515W⁴) Aminoacid position 525 (e.g., R525W)⁷* Amino acid position 531 (e.g., C531R,or 9 base pair duplication²) Amino acid position 532 (e.g.,duplication)² Amino acid position 533 (e.g., G533C, G533S) Amino acidposition 550 (e.g., G550E) Amino acid position 591 (e.g., V591I) Aminoacid position 593 (e.g., G593E) Amino acid position 595 (e.g., E595D andE595A)¹⁸ Amino acid position 600 (e.g., R600Q) Amino acid position 602(e.g., I602V)⁶ Amino acid position 603 (e.g., K603Q, K603E²) Amino acidposition 606 (e.g., Y606C) Amino acid position 609 (e.g., C609Y, C609S,C609G, C609R, C609F, C609W, C609C³²) Amino acid position 611 (e.g.,C611R, C611S, C611G, C611Y, C611F, C611W) Amino acid position 616 (e.g.,E616Q)²³ Amino acid position 618 (e.g., C618S, C618Y, C618R, C618Y,C618G, C618F, C618W) Amino acid position 619 (e.g., F619F) Amino acidposition 620 (e.g., C620S, C620W, C620R, C620G, C620L, C620Y, C620F)Amino acid position 623 (e.g., E623K) Amino acid position 624 (e.g.,D624N) Amino acid position 630 (e.g., C630A, C630R, C630S, C630Y, C630F,C630W) Amino acid position 631 (e.g., D631N, D631Y, D631A, D631G, D631V,D631E,) Amino acid position 632 (e.g., E632K, E632G^(5,11)) Δ Amino acidpositions 632-633 (6-Base Pair In-Frame Germline Deletion in Exon 11)⁹Amino acid position 633 (9 base pair duplication²) Amino acid position634 (e.g., C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, orC634T, or an insertion ELCR², or a 12 base pair duplication²) (e.g.,causing MTC) Amino acid position 635 (e.g., R635G) Amino acid position636 (e.g., T636P², T636M⁴) Amino acid position 640 (e.g., A640G) Aminoacid position 641 (e.g., A641S, A641T⁸) Amino acid position 648 (e.g.,V648I) Amino acid position 649 (e.g., S649L)²⁸ Amino acid position 664(e.g., A664D) Amino acid position 665 (e.g., H665Q) Amino acid position666 (e.g., K666E, K666M, K666N, K666R) Amino acid position 675 (T675T,silent nucleotide change)¹⁸ Amino acid position 686 (e.g., S686N) Aminoacid position 689 (e.g., S689T)¹⁸ Amino acid position 691 (e.g., G691S)Amino acid position 694 (e.g., R694Q) Amino acid position 700 (e.g.,M700L) Amino acid position 706 (e.g., V706M, V706A) Amino acid position713 splice variant (e.g., E713K)⁶ Amino acid position 732 (e.g.,E732K)²⁰ Amino acid position 736 (e.g., G736R)⁶ Amino acid position 748(e.g., G748C) Amino acid position 750 (e.g., A750P) Amino acid position765 (e.g., S765P) Amino acid position 766 (e.g., P766S, P766M⁶) Aminoacid position 768 (e.g., E768Q, E768D) Amino acid position 769 (e.g.,L769L) Amino acid position 770 (e.g., R770Q) Amino acid position 771(e.g., D771N) Amino acid position 777 (e.g., N777S) Amino acid position778 (e.g., V778I) Amino acid position 781 (e.g., Q781R) Amino acidposition 788 (e.g., I788I³²) Amino acid position 790 (e.g., L790F) Aminoacid position 791 (e.g., Y791F, Y791N²⁴) Amino acid position 802 Aminoacid position 804 (e.g., V804L^(15,16), V804M^(15,16), V804E¹²) (e.g.,causing MTC) Amino acid position 805 (e.g., E805K) Amino acid position804/805 (e.g., V804M/E805K)¹⁷ Amino acid position 806 (e.g., Y806F,Y806S¹², Y806G, Y806C^(2,12,14), Y806E¹⁴, Y806H¹², Y806N¹², Y806Y³²)Amino acid position 810 (e.g., G810R¹², G810S¹², G810A¹³) Amino acidposition 818 (e.g., E818K) Amino acid position 819 (e.g., S819I) Aminoacid position 823 (e.g., G823E) Amino acid position 826 (e.g., Y826M,Y826S)¹⁰ Amino acid position 833 (e.g., R833C) Amino acid position 836(e.g., S836S)¹⁹ Amino acid position 841 (e.g., P841L, P841P) Amino acidposition 843 (e.g., E843D) Amino acid position 844 (e.g., R844W, R844Q,R844L) Amino acid position 848 (e.g., M848T) Amino acid position 852(e.g., I852M) Amino acid position 865 (e.g., L865V)¹² Amino acidposition 870 (e.g., L870F)¹² Amino acid position 873 (e.g., R873W) Aminoacid position 876 (e.g., A876V) Amino acid position 881 (e.g., L881V)Amino acid position 882 Amino acid position 883 (e.g., A883F, A883S,A883T) Amino acid position 884 (e.g., E884K) Amino acid position 886(e.g., R886W) Amino acid position 891 (e.g., S891A, S891S³²) Amino acidposition 897 (e.g., R897Q) Amino acid position 898 (e.g., D898V) Aminoacid position 900 (e.g., Y900F)²² Amino acid position 901 (e.g., E901K)Amino acid position 904 (e.g., S904F, S904S, S904C²) Amino acid position905 (e.g., Y905F)²² Amino acid position 907 (e.g., K907E, K907M) Aminoacid position 908 (e.g., R908K) Amino acid position 911 (e.g., G911D)Amino acid position 912 (e.g., R912P, R912Q) Amino acid position 918(e.g., M918T², M918V, M918L⁶) (e.g., causing MTC) Amino acid position919 (e.g., A919V) Amino acid position 921 (e.g., E921K) Amino acidposition 922 (e.g., S922P, S922Y) Amino acid position 930 (e.g., T930M)Amino acid position 961 (e.g., F961L) Amino acid position 972 (e.g.,R972G) Amino acid position 981 (e.g., Y981F)²² Amino acid position 982(e.g., R982C) Amino acid position 1009 (e.g., M1009V) Amino acidposition 1015 (e.g., Y1015F)²² Amino acid position 1017 (e.g., D1017N)Amino acid position 1041 (e.g., V1041G) Amino acid position 1064 (e.g.,M1064T) Amino acid position 1096 (e.g., Y1096F)²¹ RET + 3¹ (In-FrameDeletion in Exons 6 and 11)²⁵ (3 bp In-Frame Deletion in Exon 15)²⁶Nucleotide position 2136 + 2 (e.g., 2136 + 2T > G)²⁹ (del632-636 ins6)³¹Amino acid positions 791 and 852 (e.g., Y791F + I852M)³¹ Amino acidpositions 634 and 852 (e.g., C634R + I852M)³¹ ¹U.S. patent applicationPub. No. 2014/0272951. ²Krampitz et al., Cancer 120: 1920-1931, 2014.³Latteyer, et al., J. Clin. Endocrinol. Metab. 101(3): 1016-22, 2016.⁴Silva, et al. Endocrine 49.2: 366-372, 2015. ⁵Scollo, et al., Endocr.J. 63(1): 87-91, 2016. ⁶Jovanovic, et al., Prilozi 36(1): 93-107, 2015.⁷Qi, et al., Oncotarget. 6(32): 33993-4003, 2015. *R525W and G513Dappear to act in combination with S891A to enchance oncogenic activity.⁸Kim, et al. ACTA ENDOCRINOLOGICA-BUCHAREST 11.2, 189-194, 2015.⁹Cecchirini, et al. Oncogene, 14, 2609-2612, 1997. ¹⁰Karrasch, et al.Eur. Thyroid J., 5(1): 73-7, 2016. ¹¹Scollo et al., Endocr. J. 63:87-91, 2016. ¹²PCT Patent Application Publication No. WO 2016/127074.¹³Huang et al., Mol. Cancer Ther., 2016 Aug. 5. pii:molcanther.0258.2016. [Epub ahead of print]. ¹⁴Carlomagno, et al.,Endocr. Rel. Cancer 16(1): 233-41, 2009. ¹⁵Yoon et al., J. Med. Chem.59(1): 358-73, 2016. ¹⁶U.S. Pat. No. 8,629,135. ¹⁷Cranston, et al.,Cancer Res. 66(20): 10179-87, 2006. ¹⁸Kheiroddin et al., Clin. Lab.62(5): 871-6, 2016. ¹⁹Ceolin et al., PLoS One. 11(2): e0147840, doi:10.1371/journal.pone.0147840, 2016. ²⁰Nadezda et al., SummerUndergraduate Research Programs (SURP) Student Abstracts, University ofOklahoma Health Sciences Center, 2016. ²¹Liu et al., J. Biol. Chem.,271(10): 5309-12, 1995. ²²Kato et al., Cancer Res., 62: 2414-22, 2002.²³Grey et al., Endocrine Pathology, doi: 10.1007/s12022-016-9451-6,2016. ²⁴De Almeida et al., Endocrine Reviews, 2016, Vol. 37, No. 2,Supp. Supplement 1. Abstract Number: SUN-068; 98^(th) Annual Meeting andExpo of the Endocrine Society, ENDO 2016. Boston, MA, US. 1 Apr. 2016-4Apr. 2016. ²⁵Vanden et al., Annals of Oncology, 2016, Vol. 27, Supp.Supplement 6. Abstract Number: 427PD; 41^(st) European Society forMedical Oncology Congress, ESMP 2016. Copenhagen, Denmark. 7 Oct.2016-11 Oct. 2016. ²⁶Romei et al., European Thyroid Journal (August2016) Vol. 5, Supp. Supplement 1, pp. 75; 39^(th) Annual Meeting of theEuropean Thyroid Association, ETA 2016. Copenhagen, Denmark. 3 Sep.2016-6 Sep. 2016. ²⁷Lee et al., Oncotarget, 8(4): 6579-6588, doi:10.18632/oncotarget.14172, 2017. ²⁸Zhang et al., LaboratoryInvestigation, (February 2017) Vol. 97, Supp. 1, pp. 209A. AbstractNumber: 840, Meeting Info: 106th Annual Meeting of the United States andCanadian Academy of Pathology, USCAP 2017. San Antonio, TX, UnitedStates. ²⁹Borecka et al., European Journal of Cancer, (July 2016) Vol.61, No. 1, pp. S26, Abstract Number: 162, Meeting Info: 24th BiennialCongress of the European Association for Cancer Research, EACR 2016.Manchester, United Kingdom. ³⁰Corsello et al., Endocrine Reviews, (JUNE2014) Vol. 35, No. 3, Suppl. S, pp. SUN-0322, Meeting Info.: 96th AnnualMeeting and Expo of the Endocrine-Society, Chicago, IL, USA, Jun. 21-24,2014. ³¹Gazizova et al., Endocrine Reviews, (JUNE 2014) Vol. 35, No. 3,Suppl. S, pp. SAT-0304, Meeting Info.: 96th Annual Meeting and Expo ofthe Endocrine-Society, Chicago, IL, USA, Jun. 21-24, 2014. ³²Sromek etal., Endocr Pathol., doi: 10.1007/s12022-017-9487-2, 2017.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a RET gene that results in the production of a RETkinase that has one or more amino acid substitutions, insertions, ordeletions as compared to the wild-type RET kinase (see, for example, thepoint mutations listed in Table 2a).

Exemplary activating RET Kinase Protein PointMutations/Insertions/Deletions Exemplary RET Point Mutations Amino acidposition 20 Amino acid position 32 (e.g., S32L) Amino acid position 34(e.g., D34S) Amino acid position 40 (e.g., L40P) Amino acid position 64(e.g., P64L) Amino acid position 67 (e.g., R67H) Amino acid position 114(e.g., R114H) Amino acid position 145 (e.g., V145G) Amino acid position200 Amino acid position 292 (e.g., V292M) Amino acid position 294 Aminoacid position 321 (e.g., G321R) Amino acid position 330 (e.g., R330Q)Amino acid position 338 (e.g., T338I) Amino acid position 360 (e.g.,R360W) Amino acid position 393 (e.g., F393L) Amino acid position 432 ΔAmino acid residues 505-506 (6-Base Pair In-Frame Germline Deletion inExon 7) Amino acid position 510 (e.g., A510V) Amino acid position 511(e.g., E511K) Amino acid position 513 (e.g., G513D) Amino acid position515 (e.g., C515S, C515W⁴) Amino acid position 525 (e.g., R525W) Aminoacid position 531 (e.g., C531R, or 9 base pair duplication) Amino acidposition 532 (e.g., duplication) Amino acid position 533 (e.g., G533C,G533S) Amino acid position 550 (e.g., G550E) Amino acid position 591(e.g., V591I) Amino acid position 593 (e.g., G593E) Amino acid position595 (e.g., E595D and E595A) Amino acid position 600 (e.g., R600Q) Aminoacid position 602 (e.g., I602V) Amino acid position 603 (e.g., K603Q,K603E) Amino acid position 606 (e.g., Y606C) Amino acid position 609(e.g., C609Y, C609S, C609G, C609R, C609F, C609W) Amino acid position 611(e.g., C611R, C611S, C611G, C611Y, C611F, C611W) Amino acid position 616(e.g., E616Q) Amino acid position 618 (e.g., C618S, C618Y, C618R, C618G,C618F, C618W) Amino acid position 620 (e.g., C620S, C620W, C620R, C620G,C620L, C620Y, C620F) Amino acid position 623 (e.g., E623K) Amino acidposition 624 (e.g., D624N) Amino acid position 630 (e.g., C630A, C630R,C630S, C630Y, C630F, C630W) Amino acid position 631 (e.g., D631N, D631Y,D631A, D631G, D631V, D631E,) Amino acid position 632 (e.g., E632K,E632G) Δ Amino acid residues 632-633 (6-Base Pair In-Frame GermlineDeletion in Exon 11) Amino acid position 633 (e.g., 9 base pairduplication) Amino acid position 634 (e.g., C634W, C634Y, C634S, C634R,C634F, C634G, C634L, C634A, or C634T, or an insertion ELCR, or a 12 basepair duplication) (e.g., causing MTC) Amino acid position 635 (e.g.,R635G) Amino acid position 636 (e.g., T636P, T636M) Amino acid position640 (e.g., A640G) Amino acid position 641 (e.g., A641S, A641T) Aminoacid position 648 (e.g., V648I) Amino acid position 649 (e.g., S649L)Amino acid position 664 (e.g., A664D) Amino acid position 665 (e.g.,H665Q) Amino acid position 666 (e.g., K666E, K666M, K666N, K666R) Aminoacid position 686 (e.g., S686N) Amino acid position 689 (e.g., S689T)Amino acid position 691 (e.g., G691S) Amino acid position 694 (e.g.,R694Q) Amino acid position 700 (e.g., M700L) Amino acid position 706(e.g., V706M, V706A) Amino acid position 713 splice variant (e.g.,E713K) Amino acid position 732 (e.g., E732K) Amino acid position 736(e.g., G736R) Amino acid position 748 (e.g., G748C) Amino acid position750 (e.g., A750P) Amino acid position 765 (e.g., S765P) Amino acidposition 766 (e.g., P766S, P766M) Amino acid position 768 (e.g., E768Q,E768D) Amino acid position 769 (e.g., L769L) Amino acid position 770(e.g., R770Q) Amino acid position 771 (e.g., D771N) Amino acid position777 (e.g., N777S) Amino acid position 778 (e.g., V778I) Amino acidposition 781 (e.g., Q781R) Amino acid position 790 (e.g., L790F) Aminoacid position 791 (e.g., Y791F, Y791N) Amino acid position 802 Aminoacid position 804 (e.g., V804L, V804M, V804E) (e.g., causing MTC) Aminoacid position 805 (e.g., E805K) Amino acid position 804/805 (e.g.,V804M/E805K) Amino acid position 806 (e.g., Y806F, Y806S, Y806G, Y806C,Y806E, Y806H, Y806N) Amino acid position 810 (e.g., G810R, G810S, G810A)Amino acid position 818 (e.g., E818K) Amino acid position 819 (e.g.,S819I) Amino acid position 823 (e.g., G823E) Amino acid position 826(e.g., Y826M, Y826S) Amino acid position 833 (e.g., R833C) Amino acidposition 836 (e.g., S836S) Amino acid position 841 (e.g., P841L, P841P)Amino acid position 843 (e.g., E843D) Amino acid position 844 (e.g.,R844W, R844Q, R844L) Amino acid position 848 (e.g., M848T) Amino acidposition 852 (e.g., I852M) Amino acid position 865 (e.g., L865V) Aminoacid position 870 (e.g., L870F) Amino acid position 873 (e.g., R873W)Amino acid position 876 (e.g., A876V) Amino acid position 881 (e.g.,L881V) Amino acid position 882 Amino acid position 883 (e.g., A883F,A883S, A883T) Amino acid position 884 (e.g., E884K) Amino acid position886 (e.g., R886W) Amino acid position 891 (e.g., S891A) Amino acidposition 897 (e.g., R897Q) Amino acid position 898 (e.g., D898V) Aminoacid position 900 (e.g., Y900F) Amino acid position 901 (e.g., E901K)Amino acid position 904 (e.g., S904F, S904S, S904C) Amino acid position907 (e.g., K907E, K907M) Amino acid position 908 (e.g., R908K) Aminoacid position 911 (e.g., G911D) Amino acid position 912 (e.g., R912P,R912Q) Amino acid position 918 (e.g., M918T, M918V, M918L) (e.g.,causing MTC) Amino acid position 919 (e.g., A919V) Amino acid position921 (e.g., E921K) Amino acid position 922 (e.g., S922P, S922Y) Aminoacid position 930 (e.g., T930M) Amino acid position 961 (e.g., F961L)Amino acid position 972 (e.g., R972G) Amino acid position 982 (e.g.,R982C) Amino acid position 1009 (e.g., M1009V) Amino acid position 1015(e.g., Y1015F) Amino acid position 1017 (e.g., D1017N) Amino acidposition 1041 (e.g., V1041G) Amino acid position 1064 (e.g., M1064T)Amino acid position 1096 (e.g., Y1096F) RET + 3 (In-Frame Deletion inExons 6 and 11) (3 bp In-Frame Deletion in Exon 15)

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes a splicevariation in a RET mRNA which results in an expressed protein that is analternatively spliced variant of RET having at least one residue deleted(as compared to the wild-type RET kinase) resulting in a constitutiveactivity of a RET kinase domain.

A “RET kinase inhibitor” as defined herein includes any compoundexhibiting RET inhibition activity. In some embodiments, a RET kinaseinhibitor is selective for a RET kinase. Exemplary RET kinase inhibitorscan exhibit inhibition activity (IC₅₀) against a RET kinase of less thanabout 1000 nM, less than about 500 nM, less than about 200 nM, less thanabout 100 nM, less than about 50 nM, less than about 25 nM, less thanabout 10 nM, or less than about 1 nM as measured in an assay asdescribed herein. In some embodiments, a RET kinase inhibitor canexhibit inhibition activity (IC₅₀) against a RET kinase of less thanabout 25 nM, less than about 10 nM, less than about 5 nM, or less thanabout 1 nM as measured in an assay as provided herein.

As used herein, a “first RET kinase inhibitor” or “first RET inhibitor”is a RET kinase inhibitor as defined herein, but which does not includea compound of Formula I or a pharmaceutically acceptable salt or solvatethereof as defined herein. As used herein, a “second RET kinaseinhibitor” or a “second RET inhibitor” is a RET kinase inhibitor asdefined herein, but which does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as defined herein.When both a first and a second RET inhibitor are present in a methodprovided herein, the first and second RET kinase inhibitor aredifferent.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a RET gene that results in the production of a RETkinase that has one or more amino acid substitutions or insertions ordeletions in a RET gene that results in the production of a RET kinasethat has one or more amino acids inserted or removed, as compared to thewild-type RET kinase. In some cases, the resulting RET kinase is moreresistant to inhibition of its phosphotransferase activity by one ormore first RET kinase inhibitor(s), as compared to a wildtype RET kinaseor a RET kinase not including the same mutation. Such mutations,optionally, do not decrease the sensitivity of the cancer cell or tumorhaving the RET kinase to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof (e.g., as comparedto a cancer cell or a tumor that does not include the particular RETinhibitor resistance mutation). In such embodiments, a RET inhibitorresistance mutation can result in a RET kinase that has one or more ofan increased V_(max), a decreased K_(m) for ATP, and an increased K_(D)for a first RET kinase inhibitor, when in the presence of a first RETkinase inhibitor, as compared to a wildtype RET kinase or a RET kinasenot having the same mutation in the presence of the same first RETkinase inhibitor.

In other embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a RET gene that results in the production of a RETkinase that has one or more amino acid substitutions as compared to thewild-type RET kinase, and which has increased resistance to a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof,as compared to a wildtype RET kinase or a RET kinase not including thesame mutation. In such embodiments, a RET inhibitor resistance mutationcan result in a RET kinase that has one or more of an increased V_(max),a decreased K_(m), and a decreased K_(D) in the presence of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof,as compared to a wildtype RET kinase or a RET kinase not having the samemutation in the presence of the same compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Examples of RET inhibitor resistance mutations can, e.g., include pointmutations, insertions, or deletions in and near the ATP binding site inthe tertiary structure of RET kinase, including but not limited to thegatekeeper residue, P-loop residues, residues in or near the DFG motif,and ATP cleft solvent front amino acid residues. Additional examples ofthese types of mutations include changes in residues that may affectenzyme activity and/or drug binding including but are not limited toresidues in the activation loop, residues near or interacting with theactivation loop, residues contributing to active or inactive enzymeconformations, changes including mutations, deletions, and insertions inthe loop proceeding the C-helix and in the C-helix. Specific residues orresidue regions that may be changed (and are RET inhibitor resistancemutations) include but are not limited to those listed in Table 3 basedon the human wildtype RET protein sequence (e.g., SEQ ID NO: 1).Additional examples of RET inhibitor resistance mutation positions areshown in Table 4. Changes to these residues may include single ormultiple amino acid changes, insertions within or flanking thesequences, and deletions within or flanking the sequences.

Exemplary Sequence of Mature Human RET Protein (SEQ ID NO: 1)

MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKLYVDQAAGTPL LYVHALRDAP EEVPSFRLGQ HLYGTYRTRLHENNWICIQE DTGLLYLNRS LDHSSWEKLS VRNRGFPLLTVYLKVFLSPT SLREGECQWP GCARVYFSFF NTSFPACSSLKPRELCFPET RPSFRIRENR PPGTFHQFRL LPVQFLCPNISVAYRLLEGE GLPFRCAPDS LEVSTRWALD REQREKYELVAVCTVHAGAR EEVVMVPFPV TVYDEDDSAP TFPAGVDTASAVVEFKRKED TVVATLRVFD ADVVPASGEL VRRYTSTLLPGDTWAQQTFR VEHWPNETSV QANGSFVRAT VHDYRLVLNRNLSISENRTM QLAVLVNDSD FQGPGAGVLL LHFNVSVLPVSLHLPSTYSL SVSRRARRFA QIGKVCVENC QAFSGINVQYKLHSSGANCS TLGVVTSAED TSGILFVNDT KALRRPKCAELHYMVVATDQ QTSRQAQAQL LVTVEGSYVA EEAGCPLSCAVSKRRLECEE CGGLGSPTGR CEWRQGDGKG ITRNFSTCSPSTKTCPDGHC DVVETQDINI CPQDCLRGSI VGGHEPGEPRGIKAGYGTCN CFPEEEKCFC EPEDIQDPLC DELCRTVIAAAVLFSFIVSV LLSAFCIHCY HKFAHKPPIS SAEMTFRRPAQAFPVSYSSS GARRPSLDSM ENQVSVDAFK ILEDPKWEFPRKNLVLGKTL GEGEFGKVVK ATAFHLKGRA GYTTVAVKMLKENASPSELR DLLSEFNVLK QVNHPHVIKL YGACSQDGPLLLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDHPDERALTMGD LISFAWQISQ GMQYLAEMKL VHRDLAARNILVAEGRKMKI SDFGLSRDVY EEDSYVKRSQ GRIPVKWMAIESLFDHIYTT QSDVWSFGVL LWEIVTLGGN PYPGIPPERLFNLLKTGHRM ERPDNCSEEM YRLMLQCWKQ EPDKRPVFADISKDLEKMMV KRRDYLDLAA STPSDSLIYD DGLSEEETPLVDCNNAPLPR ALPSTWIENK LYGMSDPNWP GESPVPLTRADGTNTGFPRY PNDSVYANWM LSPSAAKLMD TFDS

In some embodiments, compounds of Formula I and pharmaceuticallyacceptable salts and solvates are useful in treating patients thatdevelop cancers with RET inhibitor resistance mutations (e.g., thatresult in an increased resistance to a first RET inhibitor, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E,and/or one or more RET inhibitor resistance mutations listed in Tables 3and 4) by either dosing in combination or as a follow-up therapy toexisting drug treatments (e.g., other RET kinase inhibitors; e.g., firstand/or second RET kinase inhibitors). Exemplary first and second RETkinase inhibitors are described herein. In some embodiments, a first orsecond RET kinase inhibitor can be selected from the group consisting ofcabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib,dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

In some embodiments, compounds of Formula I or pharmaceuticallyacceptable salts and solvates thereof are useful for treating a cancerthat has been identified as having one or more RET inhibitor resistancemutations (that result in an increased resistance to a first or secondRET inhibitor, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E). Non-limiting examples of RET inhibitorresistance mutations are listed in Tables 3 and 4.

TABLE 3 RET Inhibitor Resistance Mutations Exemplary RET ResistanceMutations Amino acid position 732 (e.g., E732K)⁷ Amino acid position 788(e.g., I788N)⁸ Amino acid position 804 (e.g., V804M^(1,2), V804L^(1,2),V804E⁶) Amino acid position 804/805 (e.g., V804M/E805K)³ Amino acidposition 806 (e.g., Y806C^(4,6), Y806E⁴, Y806S⁶, Y806H⁶, Y806N⁶) Aminoacid position 810 (e.g., G810A⁵, G810R⁶, G810S⁶) Amino acid position 865(e.g., L865V⁶) Amino acid position 870 (e.g., L870F⁶) ¹Yoon et al., J.Med. Chem. 59(1): 358-73, 2016. ²U.S. Pat. No. 8,629,135. ³Cranston, etal., Cancer Res. 66(20): 10179-87, 2006. ⁴Carlomagno, et al., Endocr.Rel. Cancer 16(1): 233-41, 2009. ⁵Huang et al., Mol. Cancer Ther., 2016Aug. 5. pii: molcanther.0258.2016. [Epub ahead of print]. ⁶PCT PatentApplication Publication No. WO 2016/127074. ⁷Nadezda et al., SummerUndergraduate Research Programs (SURP) Student Abstracts, University ofOklahoma Health Sciences Center, 2016. ⁸Plenker et al., Sci. Transl.Med., 9(394), doi: 10.1126/scitranslmed.aah6144, 2017.

TABLE 4 Additional Exemplary Amino Acid Positions of RET InhibitorResistance Mutations RET Amino Acid and Exemplary Position MutationMechanistic Resistance Rationale L730 P Steric hindrance and/or activeconformational effect G731 V Steric hindrance and/or activeconformational effect E732 K Steric hindrance and/or activeconformational effect G733 V Steric hindrance and/or activeconformational effect E734 K Steric hindrance and/or activeconformational effect L760 M Active conformational effect K761 E Activeconformational effect E762 K Active conformational effect N763 D Activeconformational effect A764 V Active conformational effect S765 N Activeconformational effect P766 A Active conformational effect S767 C Activeconformational effect E768 K Active conformational effect L779 M Sterichindrance and/or active conformational effect I788 M Steric hindranceand/or active conformational effect M868 R Steric hindrance and/oractive conformational effect K869 E Steric hindrance and/or activeconformational effect L870 Q Steric hindrance and/or activeconformational effect V871 M Steric hindrance and/or activeconformational effect H872 R Steric hindrance and/or activeconformational effect R873 P Steric hindrance and/or activeconformational effect D874 Y Steric hindrance and/or activeconformational effect L881 R Steric hindrance and/or activeconformational effect L895 M Active conformational effect S896 N Activeconformational effect R897 C Active conformational effect D898 Y Activeconformational effect V899 G Active conformational effect Y900 D Activeconformational effect E901 K Active conformational effect E902 K Activeconformational effect D903 Y Active conformational effect S904 C Activeconformational effect Y905 D Active conformational effect V906 M Activeconformational effect K907 E Active conformational effect R908 P Activeconformational effect S909 C Active conformational effect Q910 R Activeconformational effect G911 C Active conformational effect R912 P Activeconformational effect

The oncogenic role of RET was firstly described in papillary thyroidcarcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63), which arisesfrom follicular thyroid cells and is the most common thyroid malignancy.Approximately 20-30% of PTC harbor somatic chromosomal rearrangements(translocations or inversions) linking the promoter and the 5′ portionsof constitutively expressed, unrelated genes to the RET tyrosine kinasedomain (Greco et al., Q. J. Nucl. Med. Mol. Imaging, 2009, 53, 440-54),therefore driving its ectopic expression in thyroid cells. To date, avariety of fusion partners have been identified, all providing aprotein/protein interaction domain that induces ligand-independent RETdimerization and constitutive kinase activity (see, e.g., Table 1). Therole of RET-PTC rearrangements in the pathogenesis of PTC has beenconfirmed in transgenic mice (Santoro et al., Oncogene, 1996, 12,1821-6). Recently, a 10.6 Mb pericentric inversion in chromosome 10,where RET gene maps, has been identified in about 2% of lungadenocarcinoma patients, generating different variants of the chimericgene KIF5B-RET (Ju et al., Genome Res., 2012, 22, 436-45; Kohno et al.,2012, Nature Med., 18, 375-7; Takeuchi et al., Nature Med., 2012, 18,378-81; Lipson et al., 2012, Nature Med., 18, 382-4). The fusiontranscripts are highly expressed and all the resulting chimeric proteinscontain the N-terminal portion of the coiled-coil region of KIF5B, whichmediates homodimerization, and the entire RET kinase domain. None of RETpositive patients harbor other known oncogenic alterations (such as EGFRor K-Ras mutation, ALK translocation), supporting the possibility thatKIF5B-RET fusion could be a driver mutation of lung adenocarcinoma. Theoncogenic potential of KIF5B-RET has been confirmed by transfecting thefusion gene into cultured cell lines: similarly to what has beenobserved with RET-PTC fusion proteins, KIF5B-RET is constitutivelyphosphorylated and induces NIH-3T3 transformation and IL-3 independentgrowth of BA-F3 cells. However, other RET fusion proteins have beenidentified in lung adenocarcinoma patients, such as the CCDC6-RET fusionprotein, which has been found to play a key role in the proliferation ofthe human lung adenocarcinoma cell line LC-2/ad (Journal of ThoracicOncology, 2012, 7(12): 1872-1876). RET inhibitors have been shown to beuseful in treating lung cancers involving RET rearrangements (Drilon, A.E. et al. J Clin Oncol 33, 2015 (suppl; abstr 8007)). RET fusionproteins have also been identified in patients having colorectal cancer(Song Eun-Kee, et al. International Journal of Cancer, 2015, 136:1967-1975).

Besides rearrangements of the RET sequence, gain of function pointmutations of RET proto-oncogene are also driving oncogenic events, asshown in medullary thyroid carcinoma (MTC), which arises fromparafollicular calcitonin-producing cells (de Groot, et al., EndocrineRev., 2006, 27, 535-60; Wells and Santoro, Clin. Cancer Res., 2009, 15,7119-7122). Around 25% of MTC are associated with multiple endocrineneoplasia type 2 (MEN2), a group of inherited cancer syndromes affectingneuroendocrine organs caused by germline activating point mutations ofRET. In MEN2 subtypes (MEN2A, MEN2B and Familial MTC/FMTC) RET genemutations have a strong phenotype-genotype correlation definingdifferent MTC aggressiveness and clinical manifestations of the disease.In MEN2A syndrome mutations involve one of the six cysteine residues(mainly C634) located in the cysteine-rich extracellular region, leadingto ligand-independent homodimerization and constitutive RET activation.Patients develop MTC at a young age (onset at 5-25 years) and may alsodevelop pheochromocytoma (50%) and hyperparathyroidism. MEN2B is mainlycaused by M918T mutation, which is located in the kinase domain. Thismutation constitutively activates RET in its monomeric state and alterssubstrate recognition by the kinase. MEN2B syndrome is characterized byan early onset (<1 year) and very aggressive form of MTC,pheochromocytoma (50% of patients) and ganglioneuromas. In FMTC the onlydisease manifestation is MTC, usually occurring at an adult age. Manydifferent mutations have been detected, spanning the entire RET gene.The remaining 75% of MTC cases are sporadic and about 50% of them harborRET somatic mutations: the most frequent mutation is M918T that, as inMEN2B, is associated with the most aggressive phenotype. Somatic pointmutations of RET have also been described in other tumors such ascolorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and smallcell lung carcinoma (Jpn. J. Cancer Res., 1995, 86, 1127-30).

RET signaling components have been found to be expressed in primarybreast tumors and to functionally interact with estrogen receptor-ccpathway in breast tumor cell lines (Boulay et al., Cancer Res. 2008, 68,3743-51; Plaza-Menacho et al., Oncogene, 2010, 29, 4648-57), while RETexpression and activation by GDNF family ligands could play an importantrole in perineural invasion by different types of cancer cells (Ito etal., Surgery, 2005, 138, 788-94; Gil et al., J. Natl. Cancer Inst.,2010, 102, 107-18; Iwahashi et al., Cancer, 2002, 94, 167-74).

RET is also expressed in 30-70% of invasive breast cancers, withexpression being relatively more frequent in estrogen receptor-positivetumors (Plaza-Menacho, I., et al., Oncogene, 2010, 29, 4648-4657;Esseghir, S., et al., Cancer Res., 2007, 67, 11732-11741; Morandi, A.,et al., Cancer Res., 2013, 73, 3783-3795; Gattelli, A., EMBO Mol. Med.,2013, 5, 1335-1350).

The identification of RET rearrangements has been reported in a subsetof (patient-derived xenograft) PDX established from colorectal cancer.Although the frequency of such events in colorectal cancer patientsremains to be defined, these data suggest a role of RET as a target inthis indication (Gozgit et al., AACR Annual Meeting 2014). Studies haveshown that the RET promoter is frequently methylated in colorectalcancers, and heterozygous missense mutations, which are predicted toreduce RET expression, are identified in 5-10% of cases, which suggeststhat RET might have some features of a tumor suppressor in sporadiccolon cancers (Luo, Y., et al., Oncogene, 2013, 32, 2037-2047; Sjoblom,T., et al., Science, 2006, 268-274; Cancer Genome Atlas Network, Nature,2012, 487, 330-337).

An increasing number of tumor types are now being shown to expresssubstantial levels of wild-type RET kinase that could have implicationsfor tumor progression and spread. RET is expressed in 50-65% ofpancreatic ductal carcinomas, and expression is more frequent inmetastatic and higher grade tumors (Ito, Y, et al., Surgery, 2005, 138,788-794; Zeng, Q., et al., J. Int. Med. Res. 2008, 36, 656-664).

In neoplasms of hematopoietic lineages, RET is expressed in acutemyeloid leukemia (AML) with monocytic differentiation, as well as inCMML (Gattei, V. et al., Blood, 1997, 89, 2925-2937; Gattei, V., et al.,Ann. Hematol, 1998, 77, 207-210; Camos, M., Cancer Res. 2006, 66,6947-6954). Recent studies have identified rare chromosomalrearrangements that involve RET in patients with chronic myelomonocyticleukemia (CMML). CMML is frequently associated with rearrangements ofseveral tyrosine kinases, which result in the expression of chimericcytosolic oncoproteins that lead to activation of RAS pathways(Kohlmann, A., et al., J. Clin. Oncol. 2010, 28, 2858-2865). In the caseof RET, gene fusions that link RET with BCR (BCR-RET) or with fibroblastgrowth factor receptor 1 oncogene partner (FGFR1OP-RET) weretransforming in early hematopoietic progenitor cells and could shiftmaturation of these cells towards monocytic paths, probably through theinitiation of RET-mediated RAS signaling (Ballerini, P., et al.,Leukemia, 2012, 26, 2384-2389).

RET expression has also been shown to occur in several other tumortypes, including prostate cancer, small-cell lung carcinoma, melanoma,renal cell carcinoma, and head and neck tumors (Narita, N., et al.,Oncogene, 2009, 28, 3058-3068; Mulligan, L. M., et al., GenesChromosomes Cancer, 1998, 21, 326-332; Flavin, R., et al., Urol. Oncol.,2012, 30, 900-905; Dawson, D. M., J Natl Cancer Inst, 1998, 90,519-523).

In neuroblastoma, RET expression and activation by GFLs has roles intumor cell differentiation, potentially collaborating with otherneurotrophic factor receptors to down regulate N-Myc, the expression ofwhich is a marker of poor prognosis (Hofstra, R. M., W., et al., Hum.Genet. 1996, 97, 362-364; Petersen, S. and Bogenmann, E., Oncogene,2004, 23, 213-225; Brodeur, G. M., Nature Ref Cancer, 2003, 3, 203-216).

Multitargeted inhibitors which cross react with RET are known (Borrello,M. G., et al., Expert Opin. Ther. Targets, 2013, 17(4), 403-419;International Patent Application Nos. WO 2014/141187, WO 2014/184069,and WO 2015/079251).

Accordingly, provided herein are methods for treating a patientdiagnosed with (or identified as having) a cancer that includeadministering to the patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. Also provided herein are methods for treating a patientidentified or diagnosed as having a RET-associated cancer that includeadministering to the patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof or a pharmaceutical composition thereof. In some embodiments,the patient that has been identified or diagnosed as having aRET-associated cancer through the use of a regulatory agency-approved,e.g., FDA-approved test or assay for identifying dysregulation of a RETgene, a RET kinase, or expression or activity or level of any of thesame, in a patient or a biopsy sample from the patient or by performingany of the non-limiting examples of assays described herein. In someembodiments, the test or assay is provided as a kit. In someembodiments, the cancer is a RET-associated cancer. For example, theRET-associated cancer can be a cancer that includes one or more RETinhibitor resistance mutations.

Also provided are methods for treating cancer in a patient in needthereof, the method comprising: (a) determining if the cancer in thepatient is a RET-associated cancer; and (b) if the cancer is determinedto be a RET-associated cancer, administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof. Some embodiments of these methods further includeadministering to the subject another anticancer agent (e.g., a secondRET inhibitor, a second compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or immunotherapy). In someembodiments, the subject was previously treated with a first RETinhibitor or previously treated with another anticancer treatment, e.g.,resection of the tumor or radiation therapy. In some embodiments, thepatient is determined to have a RET-associated cancer through the use ofa regulatory agency-approved, e.g., FDA-approved test or assay foridentifying dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same, in a patient or a biopsy samplefrom the patient or by performing any of the non-limiting examples ofassays described herein. In some embodiments, the test or assay isprovided as a kit. In some embodiments, the cancer is a RET-associatedcancer. For example, the RET-associated cancer can be a cancer thatincludes one or more RET inhibitor resistance mutations.

Also provided are methods of treating a patient that include performingan assay on a sample obtained from the patient to determine whether thepatient has a dysregulation of a RET gene, a RET kinase, or expressionor activity or level of any of the same, and administering (e.g.,specifically or selectively administering) a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof or a pharmaceutical composition thereof to thepatient determined to have a dysregulation of a RET gene, a RET kinase,or expression or activity or level of any of the same. Some embodimentsof these methods further include administering to the subject anotheranticancer agent (e.g., a second RET inhibitor, a second compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, orimmunotherapy). In some embodiments of these methods, the subject waspreviously treated with a first RET inhibitor or previously treated withanother anticancer treatment, e.g., resection of a tumor or radiationtherapy. In some embodiments, the patient is a patient suspected ofhaving a RET-associated cancer, a patient presenting with one or moresymptoms of a RET-associated cancer, or a patient having an elevatedrisk of developing a RET-associated cancer. In some embodiments, theassay utilizes next generation sequencing, pyrosequencing,immunohistochemistry, or break apart FISH analysis. In some embodiments,the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.Additional, non-limiting assays that may be used in these methods aredescribed herein. Additional assays are also known in the art. In someembodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same includes one or moreRET inhibitor resistance mutations.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof for use in treating a RET-associated cancer in a patientidentified or diagnosed as having a RET-associated cancer through a stepof performing an assay (e.g., an in vitro assay) on a sample obtainedfrom the patient to determine whether the patient has a dysregulation ofa RET gene, a RET kinase, or expression or activity or level of any ofthe same, where the presence of a dysregulation of a RET gene, a RETkinase, or expression or activity or level of any of the same,identifies that the patient has a RET-associated cancer. Also providedis the use of a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof for the manufacture of a medicament for treatinga RET-associated cancer in a patient identified or diagnosed as having aRET-associated cancer through a step of performing an assay on a sampleobtained from the patient to determine whether the patient has adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same where the presence of dysregulation of a RETgene, a RET kinase, or expression or activity or level of any of thesame, identifies that the patient has a RET-associated cancer. Someembodiments of any of the methods or uses described herein furtherinclude recording in the patient's clinical record (e.g., a computerreadable medium) that the patient is determined to have a dysregulationof a RET gene, a RET kinase, or expression or activity or level of anyof the same, through the performance of the assay, should beadministered a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof or a pharmaceutical composition thereof. In someembodiments, the assay utilizes next generation sequencing,pyrosequencing, immunohistochemistry, or break apart FISH analysis. Insome embodiments, the assay is a regulatory agency-approved assay, e.g.,FDA-approved kit. In some embodiments, the dysregulation of a RET gene,a RET kinase, or expression or activity or level of any of the sameincludes one or more RET inhibitor resistance mutations.

Also provided is a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of a cancerin a patient in need thereof or a patient identified or diagnosed ashaving a RET-associated cancer. Also provided is the use of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereoffor the manufacture of a medicament for treating a cancer in a patientidentified or diagnosed as having a RET-associated cancer. In someembodiments, the cancer is a RET-associated cancer, for example, aRET-associated cancer having one or more RET inhibitor resistancemutations. In some embodiments, a patient is identified or diagnosed ashaving a RET-associated cancer through the use of a regulatoryagency-approved, e.g., FDA-approved, kit for identifying dysregulationof a RET gene, a RET kinase, or expression or activity or level of anyof the same, in a patient or a biopsy sample from the sample. Asprovided herein, a RET-associated cancer includes those described hereinand known in the art.

In some embodiments of any of the methods or uses described herein, thepatient has been identified or diagnosed as having a cancer with adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same. In some embodiments of any of the methods oruses described herein, the patient has a tumor that is positive for adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same. In some embodiments of any of the methods oruses described herein, the patient can be a patient with a tumor(s) thatis positive for a dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same. In some embodimentsof any of the methods or uses described herein, the patient can be apatient whose tumors have a dysregulation of a RET gene, a RET kinase,or expression or activity or level of any of the same. In someembodiments of any of the methods or uses described herein, the patientis suspected of having a RET-associated cancer (e.g., a cancer havingone or more RET inhibitor resistance mutations). In some embodiments,provided herein are methods for treating a RET-associated cancer in apatient in need of such treatment, the method comprising a) detecting adysregulation of a RET gene, a RET kinase, or the expression or activityor level of any of the same in a sample from the patient; and b)administering a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the dysregulation of a RET gene, a RET kinase, or theexpression or activity or level of any of the same includes one or morefusion proteins. Non-limiting examples of RET gene fusion proteins aredescribed in Table 1. In some embodiments, the fusion protein isKIF5B-RET. In some embodiments, the dysregulation of a RET gene, a RETkinase, or the expression or activity or level of any of the sameincludes one or more RET kinase protein pointmutations/insertions/deletions. Non-limiting examples of RET kinaseprotein point mutations/insertions/deletions are described in Table 2.In some embodiments, the RET kinase protein pointmutations/insertions/deletions are selected from the group consisting ofM918T, M918V, C634W, V804L, and V804M. In some embodiments, thedysregulation of a RET gene, a RET kinase, or the expression or activityor level of any of the same includes one or more RET inhibitorresistance mutations. Non-limiting examples of RET inhibitor resistancemutations are described in Tables 3 and 4. In some embodiments, the RETinhibitor resistance mutation is V804M. In some embodiments, the cancerwith a dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same is determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit. In some embodiments,the tumor that is positive for a dysregulation of a RET gene, a RETkinase, or expression or activity or level of any of the same is a tumorpositive for one or more RET inhibitor resistance mutations. In someembodiments, the tumor with a dysregulation of a RET gene, a RET kinase,or expression or activity or level of any of the same is determinedusing a regulatory agency-approved, e.g., FDA-approved, assay or kit.

In some embodiments of any of the methods or uses described herein, thepatient has a clinical record indicating that the patient has a tumorthat has a dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same (e.g., a tumor having one or moreRET inhibitor resistance mutations). In some embodiments, the clinicalrecord indicates that the patient should be treated with one or more ofthe compounds of Formula I or a pharmaceutically acceptable salts orsolvates thereof or compositions provided herein. In some embodiments,the cancer with a dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same is a cancer havingone or more RET inhibitor resistance mutations. In some embodiments, thecancer with a dysregulation of a RET gene, a RET kinase, or expressionor activity or level of any of the same is determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit. In some embodiments,the tumor that is positive for a dysregulation of a RET gene, a RETkinase, or expression or activity or level of any of the same is a tumorpositive for one or more RET inhibitor resistance mutations. In someembodiments, the tumor with a dysregulation of a RET gene, a RET kinase,or expression or activity or level of any of the same is determinedusing a regulatory agency-approved, e.g., FDA-approved, assay or kit.

Also provided are methods of treating a patient that includeadministering a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof to apatient having a clinical record that indicates that the patient has adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same. Also provided is the use of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof forthe manufacture of a medicament for treating a RET-associated cancer ina patient having a clinical record that indicates that the patient has adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same. Some embodiments of these methods and uses canfurther include: a step of performing an on a sample obtained from thepatient to determine whether the patient has a dysregulation of a RETgene, a RET kinase, or expression or activity or level of any of thesame, and recording the information in a patient's clinical file (e.g.,a computer readable medium) that the patient has been identified to havea dysregulation of a RET gene, a RET kinase, or expression or activityor level of any of the same. In some embodiments, the assay is an invitro assay. For example, an assay that utilizes next generationsequencing, immunohistochemistry, or break apart FISH analysis. In someembodiments, the assay is a regulatory agency-approved, e.g.,FDA-approved, kit. In some embodiments, the dysregulation of a RET gene,RET kinase, or expression or activity or level of any of the sameincludes one or more RET inhibitor resistance mutations.

Also provided herein is a method of treating a subject. The methodincludes performing an assay on a sample obtained from the subject todetermine whether the subject has a dysregulation of a RET gene, a RETprotein, or expression or level of any of the same. The method alsoincludes administering to a subject determined to have a dysregulationof a RET gene, a RET protein, or expression or activity, or level of anyof the same a therapeutically effective amount of a compound of FormulaI or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the dysregulation in a RET gene, a RET kinase protein, orexpression or activity of the same is a gene or chromosome translocationthat results in the expression of a RET fusion protein (e.g., any of theRET fusion proteins described herein). In some embodiments, the RETfusion can be selected from a KIF5B-RET fusion and a CCDC6-RET fusion.In some embodiments, the dysregulation in a RET gene, a RET kinaseprotein, or expression or activity or level of any of the same is one ormore point mutation in the RET gene (e.g., any of the one or more of theRET point mutations described herein). The one or more point mutationsin a RET gene can result, e.g., in the translation of a RET proteinhaving one or more of the following amino acid substitutions: M918T,M918V, C634W, V804L, and V804M. In some embodiments, the dysregulationin a RET gene, a RET kinase protein, or expression or activity or levelof any of the same is one or more RET inhibitor resistance mutations(e.g., any combination of the one or more RET inhibitor resistancemutations described herein). Some embodiments of these methods furtherinclude administering to the subject another anticancer agent (e.g., asecond RET inhibitor a second compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or immunotherapy).

In some embodiments, the compounds provided herein exhibit brain and/orcentral nervous system (CNS) penetrance. Such compounds are capable ofcrossing the blood brain barrier and inhibiting a RET kinase in thebrain and/or other CNS structures. In some embodiments, the compoundsprovided herein are capable of crossing the blood brain barrier in atherapeutically effective amount. For example, treatment of a patientwith cancer (e.g., a RET-associated cancer such as a RET-associatedbrain or CNS cancer) can include administration (e.g., oraladministration) of the compound to the patient. In some suchembodiments, the compounds provided herein are useful for treating aprimary brain tumor or metastatic brain tumor. For example, thecompounds can be used in the treatment of one or more of gliomas such asglioblastoma (also known as glioblastoma multiforme), astrocytomas,oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas,medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), andcraniopharyngiomas (see, for example, the tumors listed in Louis, D. N.et al. Acta Neuropathol 131(6), 803-820 (June 2016)). In someembodiments, the brain tumor is a primary brain tumor. In someembodiments, the patient has previously been treated with anotheranticancer agent, e.g., another RET inhibitor (e.g., a compound that isnot a compound of General Formula I) or a multi-kinase inhibitor. Insome embodiments, the brain tumor is a metastatic brain tumor. In someembodiments, the patient has previously been treated with anotheranticancer agent, e.g., another RET inhibitor (e.g., a compound that isnot a compound of General Formula I) or a multi-kinase inhibitor.

Also provided are methods (e.g., in vitro methods) of selecting atreatment for a patient identified or diagnosed as having aRET-associated cancer. Some embodiments can further includeadministering the selected treatment to the patient identified ordiagnosed as having a RET-associated cancer. For example, the selectedtreatment can include administration of a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof. Some embodiments can further include a step ofperforming an assay on a sample obtained from the patient to determinewhether the patient has a dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, and identifying anddiagnosing a patient determined to have a dysregulation of a RET gene, aRET kinase, or expression or activity or level of any of the same, ashaving a RET-associated cancer. In some embodiments, the cancer is aRET-associated cancer having one or more RET inhibitor resistancemutations. In some embodiments, the patient has been identified ordiagnosed as having a RET-associated cancer through the use of aregulatory agency-approved, e.g., FDA-approved, kit for identifyingdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, in a patient or a biopsy sample from thepatient. In some embodiments, the RET-associated cancers is a cancerdescribed herein or known in the art. In some embodiments, the assay isan in vitro assay. For example, an assay that utilizes the nextgeneration sequencing, immunohistochemistry, or break apart FISHanalysis. In some embodiments, the assay is a regulatoryagency-approved, e.g., FDA-approved, kit.

Also provided herein are methods of selecting a treatment for a patient,wherein the methods include a step of performing an assay on a sampleobtained from the patient to determine whether the patient has adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same (e.g., one or more RET inhibitor resistancemutations), and identifying or diagnosing a patient determined to have adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, as having a RET-associated cancer. Someembodiments further include administering the selected treatment to thepatient identified or diagnosed as having a RET-associated cancer. Forexample, the selected treatment can include administration of atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof to the patientidentified or diagnosed as having a RET-associated cancer. In someembodiments, the assay is an in vitro assay. For example, an assay thatutilizes the next generation sequencing, immunohistochemistry, or breakapart FISH analysis. In some embodiments, the assay is a regulatoryagency-approved, e.g., FDA-approved, kit.

Also provided are methods of selecting a patient for treatment, whereinthe methods include selecting, identifying, or diagnosing a patienthaving a RET-associated cancer, and selecting the patient for treatmentincluding administration of a therapeutically-effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, identifying or diagnosing a patient ashaving a RET-associated cancer can include a step of performing an assayon a sample obtained from the patient to determine whether the patienthas a dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same, and identifying or diagnosing apatient determined to have a dysregulation of a RET gene, a RET kinase,or expression or activity or level of any of the same, as having aRET-associated cancer. In some embodiments, the method of selecting atreatment can be used as a part of a clinical study that includesadministration of various treatments of a RET-associated cancer. In someembodiments, a RET-associated cancer is a cancer having one or more RETinhibitor resistance mutations. In some embodiments, the assay is an invitro assay. For example, an assay that utilizes the next generationsequencing, immunohistochemistry, or break apart FISH analysis. In someembodiments, the assay is a regulatory agency-approved, e.g.,FDA-approved, kit. In some embodiments, the dysregulation of the RETgene, the RET kinase, or expression or activity or level of any of thesame includes one or more RET inhibitor resistance mutations.

In some embodiments of any of the methods or uses described herein, anassay used to determine whether the patient has a dysregulation of a RETgene, or a RET kinase, or expression or activity or level of any of thesame, using a sample from a patient can include, for example, nextgeneration sequencing, immunohistochemistry, fluorescence microscopy,break apart FISH analysis, Southern blotting, Western blotting, FACSanalysis, Northern blotting, and PCR-based amplification (e.g., RT-PCRand quantitative real-time RT-PCR). As is well-known in the art, theassays are typically performed, e.g., with at least one labelled nucleicacid probe or at least one labelled antibody or antigen-binding fragmentthereof. Assays can utilize other detection methods known in the art fordetecting dysregulation of a RET gene, a RET kinase, or expression oractivity or levels of any of the same (see, e.g., the references citedherein). In some embodiments, the dysregulation of the RET gene, the RETkinase, or expression or activity or level of any of the same includesone or more RET inhibitor resistance mutations. In some embodiments, thesample is a biological sample or a biopsy sample (e.g., aparaffin-embedded biopsy sample) from the patient. In some embodiments,the patient is a patient suspected of having a RET-associated cancer, apatient having one or more symptoms of a RET-associated cancer, and/or apatient that has an increased risk of developing a RET-associatedcancer)

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment or therapy in addition to compositions provided herein may be,for example, surgery, radiotherapy, and chemotherapeutic agents, such askinase inhibitors, signal transduction inhibitors and/or monoclonalantibodies. Compounds of Formula I therefore may also be useful asadjuvants to cancer treatment, that is, they can be used in combinationwith one or more additional therapies or therapeutic agents, for examplea chemotherapeutic agent that works by the same or by a differentmechanism of action.

In some embodiments of any the methods described herein, the compound ofFormula I (or a pharmaceutically acceptable salt or solvate thereof) isadministered in combination with a therapeutically effective amount ofat least one additional therapeutic agent selected from one or moreadditional therapies or therapeutic (e.g., chemotherapeutic) agents.

Non-limiting examples of additional therapeutic agents include: otherRET-targeted therapeutic agents (i.e. a first or second RET kinaseinhibitor), receptor tyrosine kinase-targeted therapeutic agents, signaltransduction pathway inhibitors, checkpoint inhibitors, modulators ofthe apoptosis pathway (e.g. obataclax); cytotoxic chemotherapeutics,angiogenesis-targeted therapies, immune-targeted agents, includingimmunotherapy, and radiotherapy.

In some embodiments, the other RET-targeted therapeutic is a multikinaseinhibitor exhibiting RET inhibition activity. In some embodiments, theother RET-targeted therapeutic inhibitor is selective for a RET kinase.Exemplary RET kinase inhibitors can exhibit inhibition activity (IC₅₀)against a RET kinase of less than about 1000 nM, less than about 500 nM,less than about 200 nM, less than about 100 nM, less than about 50 nM,less than about 25 nM, less than about 10 nM, or less than about 1 nM asmeasured in an assay as described herein. In some embodiments, a RETkinase inhibitors can exhibit inhibition activity (IC₅₀) against a RETkinase of less than about 25 nM, less than about 10 nM, less than about5 nM, or less than about 1 nM as measured in an assay as providedherein.

Non-limiting examples of RET-targeted therapeutic agents includealectinib, apatinib, cabozantinib (XL-184), dovitinib, lenvatinib,motesanib, nintedanib, ponatinib, regorafenib, sitravatinib (MGCD516),sunitinib, sorafenib, vatalanib, vandetanib, AUY-922(5-(2,4-Dihydroxy-5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide),BLU6864, BLU-667, DCC-2157, GSK3179106, NVP-AST487(1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea), PZ-1, RPI-1(1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one),RXDX-105(1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea),SPP86(1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), andTG101209(N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]-benzenesulfonamide).

Additional examples of other RET kinase inhibitors include thosedescribed in U.S. Pat. Nos. 9,150,517 and 9,149,464, and InternationalPublication No. WO 2014075035, all of which are hereby incorporated byreference. For example, in some embodiments the other RET inhibitor is acompound of formula I:

wherein R₁ is C₆-C₂₄alkyl or polyethylene glycol; or a pharmaceuticallyacceptable salt form thereof. In some embodiments, the other RETinhibitor is4-{5-[bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyricacid dodecyl ester.

Additional examples of other RET kinase inhibitors include thosedescribed in International Publication No. WO 2016127074, which ishereby incorporated by reference. For example, in some embodiments, theother RET inhibitor is a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein:

wherein Rings A and B are each independently selected from aryl,heteroaryl, cycloalkyl and heterocyclyl;

each L¹ and L² is independently selected from a bond, —(C1-C6alkylene)-, —(C2-C6alkenylene)-, —(C2-C6 alkynylene)-, —(C1-C6haloalkylene)-, —(C1-C6 heteroalkylene)-, —C(O)—, —O—, —S—, —S(O),—S(O)₂—, —N(R¹)—, —O—(C1-C6 alkylene)-, —(C1-C6 alkylene)-O—,—N(R¹)—C(O)—, —C(O)N(R¹)—, —(C1-C6 alkylene)-N(R¹)—, —N(R¹)—(C1-C6alkylene)-, —N(R¹)—C(O)—(C1-C6 alkylene)-, —(C1-C6alkylene)-N(R¹)—C(O)—, —C(O)—N(R¹)—(C1-C6 alkylene)-, —(C1-C6alkylene)-C(O)—N(R¹)—, —N(R¹)—S(O)₂—, —S(O)₂—N(R¹)—, —N(R¹)—S(O)₂—(C1-C6alkylene)-, and —S(O)₂—N(R¹)—(C1-C6 alkylene)-; wherein each alkylene,alkenylene, alkynylene, haloalkylene, and heteroalkylene isindependently substituted with 0-5 occurrences of R′;

each R^(A) and R^(B) is independently selected from C1-C6 alkyl, C1-C6alkoxy, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl,and —N(R¹)(R¹); wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl, andhydroxyalkyl is independently substituted with 0-5 occurrences of R^(a);

each R^(C) and R^(D) is independently selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, C1-C6 heteroalkyl, C1-C6haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, aryl,heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro,cyano, —C(O)R¹, —OC(O)R¹, —C(O)OR¹, —(C1-C6 alkylene)-C(O)R¹, —SR¹,—S(O)₂R¹, —S(O)₂—N(R¹)(R¹), —(C1-C6 alkylene)-S(O)₂R¹, —(C1-C6alkylene)-S(O)₂—N(R¹)(R¹), —N(R¹)(R¹)—C(O)—N(R¹)(R¹)—N(R¹)—C(O)R¹,—N(R¹)—C(O)OR¹, —(C1-C6 alkylene)-N(R¹)—C(O)R¹, —N(R¹)S(O)₂R¹, and—P(O)(R¹)(R¹); wherein each of alkyl, alkenyl, alkynyl, alkoxy,heteroalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl,heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl isindependently substituted with 0-5 occurrences of R^(a); or 2 R^(C) or 2R^(D) together with the carbon atom(s) to which they are attached form acycloalkyl or heterocyclyl ring independently substituted with 0-5occurrences of R^(a);

each R¹ is independently selected from hydrogen, hydroxyl, halo, thiol,C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each ofalkyl, thioalkyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl,cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl is independently substituted with 0-5 occurrences ofR^(b), or 2 R¹ together with the atom(s) to which they are attached forma cycloalkyl or heterocyclyl ring independently substituted with 0-5occurrences of R^(b);

each R^(a) and R^(b) is independently C1-C6 alkyl, halo, hydroxyl, C1-C6haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy,cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, haloalkyl,heteroalkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl isindependently substituted with 0-5 occurrences of R′;

each R′ is C1-C6 alkyl, C1-C6 heteroalkyl, halo, hydroxyl, C1-C6haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl or cyano; or 2 R′, togetherwith the atom(s) to which they are attached form a cycloalkyl orheterocyclyl ring;

m is 0, 1, 2, or 3;

n is 0, 1, or 2; and

p and q are each independently 0, 1, 2, 3, or 4. For example, a RETinhibitor can be selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a RET inhibitor is selected from the groupconsisting of: ABT-348(N-[4-[4-Amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl]phenyl]-N′-(3-fluorophenyl)urea);AD-57, which has the structure:

AD-80(1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea);ALW-II-41-27(N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide);Amuvatinib (MP470)(N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide);BPR1J373 (a derivative of 5-phenylthhiazol-2-ylamine-pyriminide); CLM3;doramapimod (BIRB-796)(1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea);DS-5010; famitinib(5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one);fedratinib (SAR 302503, TG101348)(N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide);GSK3179106; GSK3352589; HG-6-63-01((E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide);NVP-BBT594(5-((6-acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide);PP2(4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine);PP242(2-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol);quizartinib (AC220) (1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)urea);semaxanib (SU5416, VEGFR2 Kinase Inhibitor III)((Z)-3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one); SU4984(3-[4-(1-formylpiperazin-4-yl)benzylidenyl]-2-indolinone); Withaferin A((4J3,53,63,22R)-4,27-Dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione);XL-999((Z)-5-((1-ethylpiperidin-4-yl)amino)-3-((3-fluorophenyl)(5-methyl-1H-imidazol-2-yl)methylene)indolin-2-one);XMD15-44(N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide);Y078-DM1 (antibody drug conjugate composed of a RET antibody (Y078)linked to a derivative of the cytotoxic agent maytansine); and Y078-DM1(antibody drug conjugate composed of a RET antibody (Y078) linked to aderivative of the cytotoxic agent maytansine).

Further examples of RET inhibitors include:N-(2-fluoro-5-trifluoromethylphenyl)-N′-{4′-[(2″-benzamido)pyridin-4″-ylamino]phenyl}urea;1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(imidazo[1,2-a]pyridin-6-yl)phenyl)acetamide;N-(5-(tert-butyl)isoxazol-3-yl)-2-(3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl)acetamide;2-amino-6-{[2-(4-chlorophenyl)-2-oxoethyl]sulfanyl}-4-(3-thienyl)pyridine-3,5-dicarbonitrile;and 3-arylureidobenzylidene-indolin-2-ones.

Yet other therapeutic agents include RET inhibitors such as thosedescribed, for example, in U.S. Pat. Nos. 7,504,509; 8,012,966;8,299,057; 8,399,442; 8,067,434; 8,629,135; 8,895,744; 8,937,071;9,006,256; and 9,035,063; U.S. Publication Nos. 2015/0272958;2015/0238477; 2014/0121239; 20160176865; 2011/0053934; 2011/0301157;2010/0324065; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195;International Publication Nos. WO 2017/043550; WO 2017/026718; WO2016/037578; WO 2016/038519; WO 2016/038552; WO 2014/184069; WO2014/072220; WO 2012/053606; WO 2009/017838; WO 2008/031551; WO2007/136103; WO 2007/087245; WO 2007/057399; WO 2005/051366; WO2005/062795; and WO 2005/044835; and J. Med. Chem. 2012, 55 (10),4872-4876, all of which are hereby incorporated by reference in theirentireties.

Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targetedtherapeutic agents, include afatinib, cabozantinib, cetuximab,crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab,sunitinib, trastuzumab,1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea,AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Go 6976,GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101,TPX-0005, and TSR-011. Additional Trk targeted therapeutic agentsinclude those described in U.S. Pat. Nos. 8,450,322; 8,513,263;8,933,084; 8,791,123; 8,946,226; 8,450,322; 8,299,057; and 8,912,194;U.S. Publication No. 2016/0137654; 2015/0166564; 2015/0051222;2015/0283132; and 2015/0306086; International Publication No. WO2010/033941; WO 2010/048314; WO 2016/077841; WO 2011/146336; WO2011/006074; WO 2010/033941; WO 2012/158413; WO 2014078454; WO2014078417; WO 2014078408; WO 2014078378; WO 2014078372; WO 2014078331;WO 2014078328; WO 2014078325; WO 2014078323; WO 2014078322; WO2015175788; WO 2009/013126; WO 2013/174876; WO 2015/124697; WO2010/058006; WO 2015/017533; WO 2015/112806; WO 2013/183578; and WO2013/074518, all of which are hereby incorporated by reference in theirentireties.

Further examples of Trk inhibitors can be found in U.S. Pat. No.8,637,516, International Publication No. WO 2012/034091, U.S. Pat. No.9,102,671, International Publication No. WO 2012/116217, U.S.Publication No. 2010/0297115, International Publication No. WO2009/053442, U.S. Pat. No. 8,642,035, International Publication No. WO2009092049, U.S. Pat. No. 8,691,221, International Publication No.WO2006131952, all of which are incorporated by reference in theirentireties herein. Exemplary Trk inhibitors include GNF-4256, describedin Cancer Chemother. Pharmacol. 75(1):131-141, 2015; and GNF-5837(N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]-urea),described in ACS Med. Chem. Lett. 3(2):140-145, 2012, each of which isincorporated by reference in its entirety herein.

Additional examples of Trk inhibitors include those disclosed in U.S.Publication No. 2010/0152219, U.S. Pat. No. 8,114,989, and InternationalPublication No. WO 2006/123113, all of which are incorporated byreference in their entireties herein. Exemplary Trk inhibitors includeAZ623, described in Cancer 117(6):1321-1391, 2011; AZD6918, described inCancer Biol. Ther. 16(3):477-483, 2015; AZ64, described in CancerChemother. Pharmacol. 70:477-486, 2012; AZ-23((S)-5-Chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine),described in Mol. Cancer Ther. 8:1818-1827, 2009; and AZD7451; each ofwhich is incorporated by reference in its entirety.

A Trk inhibitor can include those described in U.S. Pat. Nos. 7,615,383;7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; 5,877,016; and5,844,092, each of which is incorporated by reference in its entirety.

Further examples of Trk inhibitors include CEP-751, described in Int. J.Cancer 72:672-679, 1997; CT327, described in Acta Derm. Venereol.95:542-548, 2015; compounds described in International Publication No.WO 2012/034095; compounds described in U.S. Pat. No. 8,673,347 andInternational Publication No. WO 2007/022999; compounds described inU.S. Pat. No. 8,338,417; compounds described in InternationalPublication No. WO 2016/027754; compounds described in U.S. Pat. No.9,242,977; compounds described in U.S. Publication No. 2016/0000783;sunitinib(N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide),as described in PLoS One 9:e95628, 2014; compounds described inInternational Publication No. WO 2011/133637; compounds described inU.S. Pat. No. 8,637,256; compounds described in Expert. Opin. Ther. Pat.24(7):731-744, 2014; compounds described in Expert Opin. Ther. Pat.19(3):305-319, 2009; (R)-2-phenylpyrrolidine substitutedimidazopyridazines, e.g., GNF-8625,(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-[2,4′-bipyridin]-2′-yl)piperidin-4-olas described in ACS Med. Chem. Lett. 6(5):562-567, 2015; GTx-186 andothers, as described in PLoS One 8(12):e83380, 2013; K252a((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one),as described in Mol. Cell Biochem. 339(1-2):201-213, 2010;4-aminopyrazolylpyrimidines, e.g., AZ-23(((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine)),as described in J. Med. Chem. 51(15):4672-4684, 2008; PHA-739358(danusertib), as described in Mol. Cancer Ther. 6:3158, 2007; Go 6976(5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile),as described in J. Neurochem. 72:919-924, 1999; GW441756((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one),as described in IJAE 115:117, 2010; milciclib (PHA-848125AC), describedin J. Carcinog. 12:22, 2013; AG-879((2E)-3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide);altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);cabozantinib(N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);lestaurtinib((5S,6S,8R)-6-Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-13(6H)-one);dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);ONO-5390556; regorafenib(4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamidehydrate); and VSR-902A; all of the references above are incorporated byreference in their entireties herein.

The ability of a Trk inhibitor to act as a TrkA, TrkB, and/or Trk Cinhibitor may be tested using the assays described in Examples A and Bin U.S. Pat. No. 8,513,263, which is incorporated herein by reference.

In some embodiments, signal transduction pathway inhibitors includeRas-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib,encorafinib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6Kpathway inhibitors (e.g. everolimus, rapamycin, perifosine,temsirolimus), and other kinase inhibitors, such as baricitinib,brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin,regorafenib, ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110,INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088,NMS-1286937, PF 477736((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1Hpyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide),PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106,RXDX 108, and TG101209(N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide).

Non-limiting examples of checkpoint inhibitors include ipilimumab,tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C,BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, andpembrolizumab.

In some embodiments, cytotoxic chemotherapeutics are selected fromarsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin,cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin,docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine,irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin,paclitaxel, pemetrexed, temozolomide, and vincristine.

Non-limiting examples of angiogenesis-targeted therapies includeaflibercept and bevacizumab.

The term “immunotherapy” refers to an agent that modulates the immunesystem. In some embodiments, an immunotherapy can increase theexpression and/or activity of a regulator of the immune system. In someembodiments, an immunotherapy can decrease the expression and/oractivity of a regulator of the immune system. In some embodiments, animmunotherapy can recruit and/or enhance the activity of an immune cell.

In some embodiments, the immunotherapy is a cellular immunotherapy(e.g., adoptive T-cell therapy, dendritic cell therapy, natural killercell therapy). In some embodiments, the cellular immunotherapy issipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101-108).In some embodiments, the cellular immunotherapy includes cells thatexpress a chimeric antigen receptor (CAR). In some embodiments, thecellular immunotherapy is a CAR-T cell therapy. In some embodiments, theCAR-T cell therapy is tisagenlecleucel (Kymriah™).

In some embodiments, the immunotherapy is an antibody therapy (e.g., amonoclonal antibody, a conjugated antibody). In some embodiments, theantibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab(Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®),edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™),ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®),oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®),obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab(Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab(Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™),cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984),nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab(Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab,urelumab, pidilizumab or amatuximab.

In some embodiments, the immunotherapy is an antibody-drug conjugate. Insome embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin(Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin(Adcetris®), ado-trastuzumab emtansine (TDM-1; Kadcyla®), mirvetuximabsoravtansine (IMGN853) or anetumab ravtansine

In some embodiments, the immunotherapy includes blinatumomab (AMG103;Blincyto®) or midostaurin (Rydapt).

In some embodiments, the immunotherapy includes a toxin. In someembodiments, the immunotherapy is denileukin diftitox (Ontak®).

In some embodiments, the immunotherapy is a cytokine therapy. In someembodiments, the cytokine therapy is an interleukin 2 (IL-2) therapy, aninterferon alpha (IFNα) therapy, a granulocyte colony stimulating factor(G-CSF) therapy, an interleukin 12 (IL-12) therapy, an interleukin 15(IL-15) therapy, an interleukin 7 (IL-7) therapy or anerythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2therapy is aldesleukin (Proleukin®). In some embodiments, the IFNαtherapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapyis filgrastim (Neupogen®).

In some embodiments, the immunotherapy is an immune checkpointinhibitor. In some embodiments, the immunotherapy includes one or moreimmune checkpoint inhibitors. In some embodiments, the immune checkpointinhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) ortremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor ispembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments,the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®)or durvalumab (Imfinzi™).

In some embodiments, the immunotherapy is mRNA-based immunotherapy. Insome embodiments, the mRNA-based immunotherapy is CV9104 (see, e.g.,Rausch et al. (2014) Human Vaccin Immunother 10(11): 3146-52; and Kubleret al. (2015) J. Immunother Cancer 3:26).

In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG)therapy.

In some embodiments, the immunotherapy is an oncolytic virus therapy. Insome embodiments, the oncolytic virus therapy is talimogenealherparepvec (T-VEC; Imlygic®).

In some embodiments, the immunotherapy is a cancer vaccine. In someembodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine.In some embodiments, the HPV vaccine is Gardasil®, Gardasil9® orCervarix®. In some embodiments, the cancer vaccine is a hepatitis Bvirus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®,Recombivax HB® or GI-13020 (Tarmogen®). In some embodiments, the cancervaccine is Twinrix® or Pediarix®. In some embodiments, the cancervaccine is BiovaxID®, Oncophage®, GVAX, ADXS 11-001, ALVAC-CEA,PROSTVAC®, Rindopepimut®, CimaVax-EGF, lapuleucel-T (APC8024;Neuvenge™), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L(Hepko-V5), DCVAX®, SCIB 1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®,DPX-Survivac, or viagenpumatucel-L (HS-110).

In some embodiments, the immunotherapy is a peptide vaccine. In someembodiments, the peptide vaccine is nelipepimut-S(E75) (NeuVax™),IMA901, or SurVaxM (SVN53-67). In some embodiments, the cancer vaccineis an immunogenic personal neoantigen vaccine (see, e.g., Ott et al.(2017) Nature 547: 217-221; Sahin et al. (2017) Nature 547: 222-226). Insome embodiments, the cancer vaccine is RGSH4K, or NEO-PV-01. In someembodiments, the cancer vaccine is a DNA-based vaccine. In someembodiments, the DNA-based vaccine is a mammaglobin-A DNA vaccine (see,e.g., Kim et al. (2016) Oncolmmunology 5(2): e1069940).

In some embodiments, immune-targeted agents are selected fromaldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab,prednisone, and sipuleucel-T.

Non-limiting examples of radiotherapy include radioiodide therapy,external-beam radiation, and radium 223 therapy.

Additional kinase inhibitors include those described in, for example,U.S. Pat. Nos. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002;8,815,901; 8,912,204; 9,260,437; 9,273,051; U.S. Publication No. US2015/0018336; International Publication No. WO 2007/002325; WO2007/002433; WO 2008/080001; WO 2008/079906; WO 2008/079903; WO2008/079909; WO 2008/080015; WO 2009/007748; WO 2009/012283; WO2009/143018; WO 2009/143024; WO 2009/014637; 2009/152083; WO2010/111527; WO 2012/109075; WO 2014/194127; WO 2015/112806; WO2007/110344; WO 2009/071480; WO 2009/118411; WO 2010/031816; WO2010/145998; WO 2011/092120; WO 2012/101032; WO 2012/139930; WO2012/143248; WO 2012/152763; WO 2013/014039; WO 2013/102059; WO2013/050448; WO 2013/050446; WO 2014/019908; WO 2014/072220; WO2014/184069; and WO 2016/075224 all of which are hereby incorporated byreference in their entireties.

Further examples of kinase inhibitors include those described in, forexample, WO 2016/081450; WO 2016/022569; WO 2016/011141; WO 2016/011144;WO 2016/011147; WO 2015/191667; WO 2012/101029; WO 2012/113774; WO2015/191666; WO 2015/161277; WO 2015/161274; WO 2015/108992; WO2015/061572; WO 2015/058129; WO 2015/057873; WO 2015/017528;WO/2015/017533; WO 2014/160521; and WO 2014/011900, each of which ishereby incorporated by reference in its entirety.

Accordingly, also provided herein is a method of treating cancer,comprising administering to a patient in need thereof a pharmaceuticalcombination for treating cancer which comprises (a) a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, (b)an additional therapeutic agent, and (c) optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use for the treatment of cancer, wherein the amounts of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof and the additional therapeutic agent are together effective intreating the cancer.

In some embodiments, the additional therapeutic agent(s) includes anyone of the above listed therapies or therapeutic agents which arestandards of care in cancers wherein the cancer has a dysregulation of aRET gene, a RET protein, or expression or activity, or level of any ofthe same.

These additional therapeutic agents may be administered with one or moredoses of the compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof, or pharmaceutical composition thereof, as partof the same or separate dosage forms, via the same or different routesof administration, and/or on the same or different administrationschedules according to standard pharmaceutical practice known to oneskilled in the art.

Also provided herein is (i) a pharmaceutical combination for treating acancer in a patient in need thereof, which comprises (a) a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, (b)at least one additional therapeutic agent (e.g., any of the exemplaryadditional therapeutic agents described herein or known in the art), and(c) optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of cancer,wherein the amounts of the compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof and of the additional therapeuticagent are together effective in treating the cancer; (ii) apharmaceutical composition comprising such a combination; (iii) the useof such a combination for the preparation of a medicament for thetreatment of cancer; and (iv) a commercial package or product comprisingsuch a combination as a combined preparation for simultaneous, separateor sequential use; and to a method of treatment of cancer in a patientin need thereof. In one embodiment the patient is a human. In someembodiments, the cancer is a RET-associated cancer. For example, aRET-associated cancer having one or more RET inhibitor resistancemutations.

The term “pharmaceutical combination”, as used herein, refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and at least one additional therapeutic agent (e.g.,a chemotherapeutic agent), are both administered to a patientsimultaneously in the form of a single composition or dosage. The term“non-fixed combination” means that a compound of Formula I or apharmaceutically acceptable salt or solvate thereof and at least oneadditional therapeutic agent (e.g., chemotherapeutic agent) areformulated as separate compositions or dosages such that they may beadministered to a patient in need thereof simultaneously, concurrentlyor sequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the patient. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients

Accordingly, also provided herein is a method of treating a cancer,comprising administering to a patient in need thereof a pharmaceuticalcombination for treating cancer which comprises (a) a compound ofFormula I or pharmaceutically acceptable salt or solvate thereof, (b) anadditional therapeutic agent, and (c) optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use for the treatment of cancer, wherein the amounts of thecompound of Formula I or pharmaceutically acceptable salt or solvatethereof and the additional therapeutic agent are together effective intreating the cancer. In one embodiment, the compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as separate dosages.In one embodiment, the compound of Formula I or pharmaceuticallyacceptable salt or solvate thereof, and the additional therapeutic agentare administered as separate dosages sequentially in any order, injointly therapeutically effective amounts, e.g. in daily orintermittently dosages. In one embodiment, the compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as a combined dosage.In some embodiments, the cancer is a RET-associated cancer. For example,a RET-associated cancer having one or more RET inhibitor resistancemutations.

Also provided herein is a method of treating a disease or disordermediated by RET in a patient in need of such treatment, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof or a pharmaceutical composition thereof. In someembodiments, the disease or disorder mediated by RET is a dysregulationof RET gene, a RET kinase, or expression or activity or level of any ofthe same. For example the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same includes one or moreRET inhibitor resistance mutations. A disease or disorder mediated byRET can include any disease, disorder or condition that is directly orindirectly linked to expression or activity of RET, includingoverexpression and/or abnormal activity levels. In one embodiment, thedisease is cancer (e.g., a RET-associated cancer). In one embodiment,the cancer is any of the cancers or RET-associated cancers describedherein.

Although the genetic basis of tumorigenesis may vary between differentcancer types, the cellular and molecular mechanisms required formetastasis appear to be similar for all solid tumor types. During ametastatic cascade, the cancer cells lose growth inhibitory responses,undergo alterations in adhesiveness and produce enzymes that can degradeextracellular matrix components. This leads to detachment of tumor cellsfrom the original tumor, infiltration into the circulation through newlyformed vasculature, migration and extravasation of the tumor cells atfavorable distant sites where they may form colonies. A number of geneshave been identified as being promoters or suppressors of metastasis.For example, overexpression of glial cell-derived neurotrophic factor(GDNF) and its RET receptor tyrosine kinase have been correlated withcancer proliferation and metastasis. See, e.g., Zeng, Q. et al. J. Int.Med. Res. (2008) 36(4): 656-64.

Accordingly, also provided herein are methods for inhibiting,preventing, aiding in the prevention, or decreasing the symptoms ofmetastasis of a cancer in a patient in need thereof, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof or a pharmaceutical composition thereof. Such methodscan be used in the treatment of one or more of the cancers describedherein. See, e.g., US Publication No. 2013/0029925; InternationalPublication No. WO 2014/083567; and U.S. Pat. No. 8,568,998. In someembodiments, the cancer is a RET-associated cancer. In some embodiments,the compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof is used in combination with an additional therapy oranother therapeutic agent, including a chemotherapeutic agent, such as akinase inhibitor. For example, a first or second RET kinase inhibitor.

The term “metastasis” is an art known term and means the formation of anadditional tumor (e.g., a solid tumor) at a site distant from a primarytumor in a subject or patient, where the additional tumor includes thesame or similar cancer cells as the primary tumor.

Also provided are methods of decreasing the risk of developing ametastasis or an additional metastasis in a patient having aRET-associated cancer that include: selecting, identifying, ordiagnosing a patient as having a RET-associated cancer, andadministering a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof tothe patient selected, identified, or diagnosed as having aRET-associated cancer. Also provided are methods of decreasing the riskof developing a metastasis or an additional metastasis in a patienthaving a RET-associated cancer that includes administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvent thereof to a patient havinga RET-associated cancer. The decrease in the risk of developing ametastasis or an additional metastasis in a patient having aRET-associated cancer can be compared to the risk of developing ametastasis or an additional metastasis in the patient prior totreatment, or as compared to a patient or a population of patientshaving a similar or the same RET-associated cancer that has received notreatment or a different treatment. In some embodiments, theRET-associated cancer is a RET-associated cancer having one or more RETinhibitor resistance mutations.

The phrase “risk of developing a metastasis” means the risk that asubject or patient having a primary tumor will develop an additionaltumor (e.g., a solid tumor) at a site distant from a primary tumor in asubject or patient over a set period of time, where the additional tumorincludes the same or similar cancer cells as the primary tumor. Methodsfor reducing the risk of developing a metastasis in a subject or patienthaving a cancer are described herein.

The phrase “risk of developing additional metastases” means the riskthat a subject or patient having a primary tumor and one or moreadditional tumors at sites distant from the primary tumor (where the oneor more additional tumors include the same or similar cancer cells asthe primary tumor) will develop one or more further tumors distant fromthe primary tumor, where the further tumors include the same or similarcancer cells as the primary tumor. Methods for reducing the risk ofdeveloping additional metastasis are described herein.

As used herein, a “first RET kinase inhibitor” or “first RET inhibitor”is a RET kinase inhibitor as defined herein, but which does not includea compound of Formula I or a pharmaceutically acceptable salt or solvatethereof as defined herein. As used herein, a “second RET kinaseinhibitor” or a “second RET inhibitor” is a RET kinase inhibitor asdefined herein, but which does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as defined herein.When both a first and a second RET inhibitor are present in a methodprovided herein, the first and second RET kinase inhibitor aredifferent.

In some embodiments, the presence of one or more RET inhibitorresistance mutations in a tumor causes the tumor to be more resistant totreatment with a first RET inhibitor. Methods useful when a RETinhibitor resistance mutation causes the tumor to be more resistant totreatment with a first RET inhibitor are described below. For example,provided herein are methods of treating a subject having a cancer thatinclude: identifying a subject having a cancer cell that has one or moreRET inhibitor resistance mutations; and administering to the identifiedsubject a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the compound of Formula I or apharmaceutically acceptable salt or solvate thereof is administered incombination with the first RET inhibitor. Also provided are methods oftreating a subject identified as having a cancer cell that has one ormore RET inhibitor resistance mutations that include administering tothe subject a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof is administeredin combination with the first RET inhibitor. In some embodiments, theone or more RET inhibitor resistance mutations confer increasedresistance to a cancer cell or tumor to treatment with the first RETinhibitor. In some embodiments, the one or more RET inhibitor resistancemutations include one or more RET inhibitor resistance mutations listedin Tables 3 and 4. For example, the one or more RET inhibitor resistancemutations can include a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E.

For example, provided herein are methods for treating a RET-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a RET gene, a RET kinase, or the expressionor activity or level of any of the same in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a first RET inhibitor, wherein the first RET inhibitor is selectedfrom the group consisting of cabozantinib, vandetanib, alectinib,sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib,BLU667, and BLU6864. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has at least one RET inhibitor resistance mutation; and(d) administering a compound of Formula I, or a pharmaceuticallyacceptable salt of solvate thereof as a monotherapy or in conjunctionwith another anticancer agent to the subject if the subject has a cancercell that has at least one RET inhibitor resistance mutation; or (e)administering additional doses of the first RET inhibitor of step (b) tothe subject if the subject has a cancer cell that does not have a RETinhibitor resistance mutation. In some embodiments, provided herein aremethods for treating a RET-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting a dysregulation of aRET gene, a RET kinase, or the expression or activity or level of any ofthe same in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a first RET inhibitor,wherein the first RET inhibitor is selected from the group consisting ofcabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib,dovitinib, sunitinib, foretinib, BLU667, and BLU6864. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone RET inhibitor resistance mutation; and (d) administering a compoundof Formula I selected from i) Example No. 1-20; ii) Example No. 21-40;iii) Example No. 41-49; iv) Example No. 50-70; v) Example No. 71-89; vi)Example No. 90-109; vii) Example No. 110-129; viii) Example No. 130-149;ix) Example No. 150-169; x) Example No. 170-189; xi) Example No.190-209; xii) Example No. 210-229; xiii) Example No. 230-249; xiv)Example No. 250-259; xv) Example No. 270-289; xvi) Example No. 290-309;xvii) Example No. 310-329; xviii) Example No. 330-349; xix) Example No.350-369; xx) Example No. 370-384; xxi) Example No. 385-394; xxii)Example No. 395-407; xxiii) Example No. 408-427; xxiii) Example No.428-447; xxiv) Example No. 448-467; or xxvi) Example No. 468-488; xxvii)Example No. 489-509; xxviii) Example No. 510-530; xxvix) Example No.531-551; xxx) Example No. 552-572; xxxi) Example No. 573-593; xxxii)Example No. 594-614; xxxiii) Example No. 615-635; xxxiv) Example No.636-686; xxxv) Example No. 687-707; xxxvi) Example No. 708-728; xxxvii)Example No. 729-749; xxxviii) Example No. 750-770; xxxix) Example No.771-791; xl) Example No. 792-812; xli) Example No. 813-819, or apharmaceutically acceptable salt of solvate thereof as a monotherapy orin conjunction with another anticancer agent to the subject if thesubject has a cancer cell that has at least one RET inhibitor resistancemutation; or (e) administering additional doses of the first RETinhibitor of step (b) to the subject if the subject has a cancer cellthat does not have a RET inhibitor resistance mutation. In someembodiments, provided herein are methods for treating a RET-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting one or more fusion proteins of Table 1 and/or one or more RETkinase protein point mutations/insertions/deletions of Table 2 in asample from the subject; and (b) administering to the subject atherapeutically effective amount of a first RET inhibitor, wherein thefirst RET inhibitor is selected from the group consisting ofcabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib,dovitinib, sunitinib, foretinib, BLU667, and BLU6864. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has at leastone RET inhibitor resistance mutation of Tables 3 or 4; and (d)administering a compound of Formula I selected from i) Example No. 1-20;ii) Example No. 21-40; iii) Example No. 41-49; iv) Example No. 50-70; v)Example No. 71-89; vi) Example No. 90-109; vii) Example No. 110-129;viii) Example No. 130-149; ix) Example No. 150-169; x) Example No.170-189; xi) Example No. 190-209; xii) Example No. 210-229; xiii)Example No. 230-249; xiv) Example No. 250-259; xv) Example No. 270-289;xvi) Example No. 290-309; xvii) Example No. 310-329; xviii) Example No.330-349; xix) Example No. 350-369; xx) Example No. 370-384; xxi) ExampleNo. 385-394; xxii) Example No. 395-407; xxiii) Example No. 408-427;xxiii) Example No. 428-447; xxiv) Example No. 448-467; or xxvi) ExampleNo. 468-488; xxvii) Example No. 489-509; xxviii) Example No. 510-530;xxvix) Example No. 531-551; xxx) Example No. 552-572; xxxi) Example No.573-593; xxxii) Example No. 594-614; xxxiii) Example No. 615-635; xxxiv)Example No. 636-686; xxxv) Example No. 687-707; xxxvi) Example No.708-728; xxxvii) Example No. 729-749; xxxviii) Example No. 750-770;xxxix) Exampne No. 771-791; xl) Example No. 792-812; xli) Example No.813-819, or a pharmaceutically acceptable salt of solvate thereof as amonotherapy or in conjunction with another anticancer agent to thesubject if the subject has a cancer cell that has at least one RETinhibitor resistance mutation; or (e) administering additional doses ofthe first RET inhibitor of step (b) to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation. Insome embodiments, provided herein are methods for treating aRET-associated cancer in a subject in need of such treatment, the methodcomprising (a) detecting the fusion protein KIF5B-RET in a sample fromthe subject; and (b) administering to the subject a therapeuticallyeffective amount of a first RET inhibitor, wherein the first RETinhibitor is selected from the group consisting of cabozantinib,vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib,sunitinib, foretinib, BLU667, and BLU6864. In some embodiments, themethods further comprise (after (b)) (c) determining whether a cancercell in a sample obtained from the subject has the RET inhibitorresistance mutation V804M; and (d) administering a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof selected fromthe group consisting of a compound of Formula I selected from i) ExampleNo. 1-20; ii) Example No. 21-40; iii) Example No. 41-49; iv) Example No.50-70; v) Example No. 71-89; vi) Example No. 90-109; vii) Example No.110-129; viii) Example No. 130-149; ix) Example No. 150-169; x) ExampleNo. 170-189; xi) Example No. 190-209; xii) Example No. 210-229; xiii)Example No. 230-249; xiv) Example No. 250-259; xv) Example No. 270-289;xvi) Example No. 290-309; xvii) Example No. 310-329; xviii) Example No.330-349; xix) Example No. 350-369; xx) Example No. 370-384; xxi) ExampleNo. 385-394; xxii) Example No. 395-407; xxiii) Example No. 408-427;xxiii) Example No. 428-447; xxiv) Example No. 448-467; or xxvi) ExampleNo. 468-488; xxvii) Example No. 489-509; xxviii) Example No. 510-530;xxvix) Example No. 531-551; xxx) Example No. 552-572; xxxi) Example No.573-593; xxxii) Example No. 594-614; xxxiii) Example No. 615-635; xxxiv)Example No. 636-686; xxxv) Example No. 687-707; xxxvi) Example No.708-728; xxxvii) Example No. 729-749; xxxviii) Example No. 750-770;xxxix) Exampne No. 771-791; xl) Example No. 792-812; xli) Example No.813-819, or a pharmaceutically acceptable salt of solvate thereof as amonotherapy or in conjunction with another anticancer agent to thesubject if the subject has a cancer cell that has at least one RETinhibitor resistance mutation; or (e) administering additional doses ofthe first RET inhibitor of step (b) to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation.

As another example, provided herein are methods for treating aRET-associated cancer in a subject in need of such treatment, the methodcomprising (a) detecting a dysregulation of a RET gene, a RET kinase, orthe expression or activity or level of any of the same in a sample fromthe subject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt of solvate thereof. In some embodiments, the methodsfurther comprise (after (b)) (c) determining whether a cancer cell in asample obtained from the subject has at least one RET inhibitorresistance mutation; and (d) administering a second RET inhibitor,wherein the second RET inhibitor is selected from the group consistingof cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib,ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864, as amonotherapy or in conjunction with another anticancer agent to thesubject if the subject has a cancer cell that has at least one RETinhibitor resistance mutation; or (e) administering additional doses ofthe compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof of step (b) to the subject if the subject has a cancercell that does not have a RET inhibitor resistance mutation. In someembodiments, provided herein are methods for treating a RET-associatedcancer in a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a RET gene, a RET kinase, or the expressionor activity or level of any of the same in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I selected from i) Example No. 1-20; ii)Example No. 21-40; iii) Example No. 41-49; iv) Example No. 50-70; v)Example No. 71-89; vi) Example No. 90-109; vii) Example No. 110-129;viii) Example No. 130-149; ix) Example No. 150-169; x) Example No.170-189; xi) Example No. 190-209; xii) Example No. 210-229; xiii)Example No. 230-249; xiv) Example No. 250-259; xv) Example No. 270-289;xvi) Example No. 290-309; xvii) Example No. 310-329; xviii) Example No.330-349; xix) Example No. 350-369; xx) Example No. 370-384; xxi) ExampleNo. 385-394; xxii) Example No. 395-407; xxiii) Example No. 408-427;xxiii) Example No. 428-447; xxiv) Example No. 448-467; or xxvi) ExampleNo. 468-488; xxvii) Example No. 489-509; xxviii) Example No. 510-530;xxvix) Example No. 531-551; xxx) Example No. 552-572; xxxi) Example No.573-593; xxxii) Example No. 594-614; xxxiii) Example No. 615-635; xxxiv)Example No. 636-686; xxxv) Example No. 687-707; xxxvi) Example No.708-728; xxxvii) Example No. 729-749; xxxviii) Example No. 750-770;xxxix) Exampne No. 771-791; xl) Example No. 792-812; xli) Example No.813-819, or a pharmaceutically acceptable salt of solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one RET inhibitor resistance mutation; and (d)administering a second RET inhibitor, wherein the second RET inhibitoris selected from the group consisting of cabozantinib, vandetanib,alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib,foretinib, BLU667, and BLU6864, as a monotherapy or in conjunction withanother anticancer agent to the subject if the subject has a cancer cellthat has at least one RET inhibitor resistance mutation; or (e)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject if the subject has a cancer cell that does not have a RETinhibitor resistance mutation. In some embodiments, provided herein aremethods for treating a RET-associated cancer in a subject in need ofsuch treatment, the method comprising (a) detecting one or more fusionproteins of Table 1 and/or one or more RET kinase protein pointmutations/insertions/deletions of Table 2 in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I selected from i) Example No. 1-20; ii)Example No. 21-40; iii) Example No. 41-49; iv) Example No. 50-70; v)Example No. 71-89; vi) Example No. 90-109; vii) Example No. 110-129;viii) Example No. 130-149; ix) Example No. 150-169; x) Example No.170-189; xi) Example No. 190-209; xii) Example No. 210-229; xiii)Example No. 230-249; xiv) Example No. 250-259; xv) Example No. 270-289;xvi) Example No. 290-309; xvii) Example No. 310-329; xviii) Example No.330-349; xix) Example No. 350-369; xx) Example No. 370-384; xxi) ExampleNo. 385-394; xxii) Example No. 395-407; xxiii) Example No. 408-427;xxiii) Example No. 428-447; xxiv) Example No. 448-467; or xxvi) ExampleNo. 468-488; xxvii) Example No. 489-509; xxviii) Example No. 510-530;xxvix) Example No. 531-551; xxx) Example No. 552-572; xxxi) Example No.573-593; xxxii) Example No. 594-614; xxxiii) Example No. 615-635; xxxiv)Example No. 636-686; xxxv) Example No. 687-707; xxxvi) Example No.708-728; xxxvii) Example No. 729-749; xxxviii) Example No. 750-770;xxxix) Exampne No. 771-791; xl) Example No. 792-812; xli) Example No.813-819, or a pharmaceutically acceptable salt of solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one RET inhibitor resistance mutation of Tables 3 or 4; and(d) administering a second RET inhibitor, wherein the second RETinhibitor is selected from the group consisting of cabozantinib,vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib,sunitinib, foretinib, BLU667, and BLU6864, as a monotherapy or inconjunction with another anticancer agent to the subject if the subjecthas a cancer cell that has at least one RET inhibitor resistancemutation; or (e) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (b) to the subject if the subject has a cancer cell that does nothave a RET inhibitor resistance mutation. In some embodiments, providedherein are methods for treating a RET-associated cancer in a subject inneed of such treatment, the method comprising (a) detecting the fusionprotein KIF5B-RET in a sample from the subject; and (b) administering tothe subject a therapeutically effective amount of a compound of FormulaI selected from i) Example No. 1-20; ii) Example No. 21-40; iii) ExampleNo. 41-49; iv) Example No. 50-70; v) Example No. 71-89; vi) Example No.90-109; vii) Example No. 110-129; viii) Example No. 130-149; ix) ExampleNo. 150-169; x) Example No. 170-189; xi) Example No. 190-209; xii)Example No. 210-229; xiii) Example No. 230-249; xiv) Example No.250-259; xv) Example No. 270-289; xvi) Example No. 290-309; xvii)Example No. 310-329; xviii) Example No. 330-349; xix) Example No.350-369; xx) Example No. 370-384; xxi) Example No. 385-394; xxii)Example No. 395-407; xxiii) Example No. 408-427; xxiii) Example No.428-447; xxiv) Example No. 448-467; or xxvi) Example No. 468-488; xxvii)Example No. 489-509; xxviii) Example No. 510-530; xxvix) Example No.531-551; xxx) Example No. 552-572; xxxi) Example No. 573-593; xxxii)Example No. 594-614; xxxiii) Example No. 615-635; xxxiv) Example No.636-686; xxxv) Example No. 687-707; xxxvi) Example No. 708-728; xxxvii)Example No. 729-749; xxxviii) Example No. 750-770; xxxix) Exampne No.771-791; xl) Example No. 792-812; xli) Example No. 813-819, or apharmaceutically acceptable salt of solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has the RETinhibitor resistance mutation V804M; and (d) administering a second RETinhibitor, wherein the second RET inhibitor is selected from the groupconsisting of cabozantinib, vandetanib, alectinib, sorafenib,lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, andBLU6864, as a monotherapy or in conjunction with another anticanceragent to the subject if the subject has a cancer cell that has at leastone RET inhibitor resistance mutation; or (e) administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (b) to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation.

Also, provided herein are methods for treating a RET-associated cancerin a subject in need of such treatment, the method comprising (a)detecting a dysregulation of a RET gene, a RET kinase, or the expressionor activity or level of any of the same in a sample from the subject;and (b) administering to the subject a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the methods further comprise(after (b)) (c) determining whether a cancer cell in a sample obtainedfrom the subject has at least one RET inhibitor resistance mutation; and(d) administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with another anticancer agent(e.g., a second RET inhibitor, a second compound of Formula I or apharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation) if the subject has acancer cell that has at least one RET inhibitor resistance mutation. Insome embodiments, provided herein are methods for treating aRET-associated cancer in a subject in need of such treatment, the methodcomprising (a) detecting a dysregulation of a RET gene, a RET kinase, orthe expression or activity or level of any of the same in a sample fromthe subject; and (b) administering to the subject a therapeuticallyeffective amount of a compound of Formula I selected from i) Example No.1-20; ii) Example No. 21-40; iii) Example No. 41-49; iv) Example No.50-70; v) Example No. 71-89; vi) Example No. 90-109; vii) Example No.110-129; viii) Example No. 130-149; ix) Example No. 150-169; x) ExampleNo. 170-189; xi) Example No. 190-209; xii) Example No. 210-229; xiii)Example No. 230-249; xiv) Example No. 250-259; xv) Example No. 270-289;xvi) Example No. 290-309; xvii) Example No. 310-329; xviii) Example No.330-349; xix) Example No. 350-369; xx) Example No. 370-384; xxi) ExampleNo. 385-394; xxii) Example No. 395-407; xxiii) Example No. 408-427;xxiii) Example No. 428-447; xxiv) Example No. 448-467; or xxvi) ExampleNo. 468-488; xxvii) Example No. 489-509; xxviii) Example No. 510-530;xxvix) Example No. 531-551; xxx) Example No. 552-572; xxxi) Example No.573-593; xxxii) Example No. 594-614; xxxiii) Example No. 615-635; xxxiv)Example No. 636-686; xxxv) Example No. 687-707; xxxvi) Example No.708-728; xxxvii) Example No. 729-749; xxxviii) Example No. 750-770;xxxix) Exampne No. 771-791; xl) Example No. 792-812; xli) Example No.813-819, or a pharmaceutically acceptable salt of solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one RET inhibitor resistance mutation; and (d)administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with another anticancer agent(e.g., a second RET inhibitor, a second compound of Formula I or apharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation) if the subject has acancer cell that has at least one RET inhibitor resistance mutation. Insome embodiments, provided herein are methods for treating aRET-associated cancer in a subject in need of such treatment, the methodcomprising (a) detecting one or more fusion proteins of Table 1 and/orone or more RET kinase protein point mutations/insertions/deletions ofTable 2 in a sample from the subject; and (b) administering to thesubject a therapeutically effective amount of a compound of Formula I ora pharmaceutically acceptable salt or solvate thereof selected from thegroup consisting of a compound of Formula I selected from i) Example No.1-20; ii) Example No. 21-40; iii) Example No. 41-49; iv) Example No.50-70; v) Example No. 71-89; vi) Example No. 90-109; vii) Example No.110-129; viii) Example No. 130-149; ix) Example No. 150-169; x) ExampleNo. 170-189; xi) Example No. 190-209; xii) Example No. 210-229; xiii)Example No. 230-249; xiv) Example No. 250-259; xv) Example No. 270-289;xvi) Example No. 290-309; xvii) Example No. 310-329; xviii) Example No.330-349; xix) Example No. 350-369; xx) Example No. 370-384; xxi) ExampleNo. 385-394; xxii) Example No. 395-407; xxiii) Example No. 408-427;xxiii) Example No. 428-447; xxiv) Example No. 448-467; or xxvi) ExampleNo. 468-488; xxvii) Example No. 489-509; xxviii) Example No. 510-530;xxvix) Example No. 531-551; xxx) Example No. 552-572; xxxi) Example No.573-593; xxxii) Example No. 594-614; xxxiii) Example No. 615-635; xxxiv)Example No. 636-686; xxxv) Example No. 687-707; xxxvi) Example No.708-728; xxxvii) Example No. 729-749; xxxviii) Example No. 750-770;xxxix) Exampne No. 771-791; xl) Example No. 792-812; xli) Example No.813-819, or a pharmaceutically acceptable salt of solvate thereof. Insome embodiments, the methods further comprise (after (b)) (c)determining whether a cancer cell in a sample obtained from the subjecthas at least one RET inhibitor resistance mutation of Tables 3 or 4; and(d) administering additional doses of the compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (b) to thesubject as a monotherapy or in conjunction with another anticancer agent(e.g., a second RET inhibitor, a second compound of Formula I or apharmaceutically acceptable salt thereof, or immunotherapy) oranticancer therapy (e.g., surgery or radiation) if the subject has acancer cell that has at least one RET inhibitor resistance mutation. Insome embodiments, a second RET inhibitor selected from the groupconsisting of cabozantinib, vandetanib, alectinib, sorafenib,lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, andBLU6864 is administered in step (d). In some embodiments, providedherein are methods for treating a RET-associated cancer in a subject inneed of such treatment, the method comprising (a) detecting the fusionprotein KIF5B-RET in a sample from the subject; and (b) administering tothe subject a therapeutically effective amount of a compound of FormulaI selected from i) Example No. 1-20; ii) Example No. 21-40; iii) ExampleNo. 41-49; iv) Example No. 50-70; v) Example No. 71-89; vi) Example No.90-109; vii) Example No. 110-129; viii) Example No. 130-149; ix) ExampleNo. 150-169; x) Example No. 170-189; xi) Example No. 190-209; xii)Example No. 210-229; xiii) Example No. 230-249; xiv) Example No.250-259; xv) Example No. 270-289; xvi) Example No. 290-309; xvii)Example No. 310-329; xviii) Example No. 330-349; xix) Example No.350-369; xx) Example No. 370-384; xxi) Example No. 385-394; xxii)Example No. 395-407; xxiii) Example No. 408-427; xxiii) Example No.428-447; xxiv) Example No. 448-467; or xxvi) Example No. 468-488; xxvii)Example No. 489-509; xxviii) Example No. 510-530; xxvix) Example No.531-551; xxx) Example No. 552-572; xxxi) Example No. 573-593; xxxii)Example No. 594-614; xxxiii) Example No. 615-635; xxxiv) Example No.636-686; xxxv) Example No. 687-707; xxxvi) Example No. 708-728; xxxvii)Example No. 729-749; xxxviii) Example No. 750-770; xxxix) Exampne No.771-791; xl) Example No. 792-812; xli) Example No. 813-819, or apharmaceutically acceptable salt of solvate thereof. In someembodiments, the methods further comprise (after (b)) (c) determiningwhether a cancer cell in a sample obtained from the subject has the RETinhibitor resistance mutation V804M; and (d) administering additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (b) to the subject as a monotherapy or inconjunction with another anticancer agent (e.g., a second RET inhibitor,a second compound of Formula I or a pharmaceutically acceptable saltthereof, or immunotherapy) or anticancer therapy (e.g., surgery orradiation) if the subject has a cancer cell that has at least one RETinhibitor resistance mutation. In some embodiments, a second RETinhibitor selected from the group consisting of cabozantinib,vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib,sunitinib, foretinib, BLU667, and BLU6864 is administered in step (d).

Also provided are methods of selecting a treatment for a subject havinga cancer that include: identifying a subject having a cancer cell thathas one or more RET inhibitor resistance mutations; and selecting atreatment that includes administration of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the one or more RET inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with a firstRET inhibitor. In some embodiments, the compound of Formula I or apharmaceutically acceptable salt or solvate thereof is administered incombination with the first RET inhibitor. Also provided are methods ofselecting a treatment for a subject having a cancer that include:selecting a treatment that includes administration of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof for asubject identified as having a cancer cell that has one or more RETinhibitor resistance mutations. Also provided are methods of selecting asubject having a cancer for a treatment that does not include a firstRET inhibitor as a monotherapy that include: identifying a subjecthaving a cancer cell that has one or more RET inhibitor resistancemutations; and selecting the identified subject for a treatment thatincludes a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof. Also provided are methods of selecting a subjecthaving a cancer for a treatment that does not include a first RETinhibitor as a monotherapy that include: selecting a subject identifiedas having a cancer cell that has one or more RET inhibitor resistancemutations for a treatment that includes administration of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the one or more RET inhibitor resistance mutationsinclude one or more RET inhibitor resistance mutations listed in Tables3 and 4. In some embodiments, the one or more RET inhibitor resistancemutations can include a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E.

Also provided are methods of determining the likelihood that a subjecthaving a cancer (e.g., a RET-associated cancer) will have a positiveresponse to treatment with a first RET inhibitor as a monotherapy thatinclude: determining whether a cancer cell in a sample obtained from thesubject has one or more RET inhibitor resistance mutations; anddetermining that a subject having a cancer cell that has one or more RETinhibitor resistance mutations has a decreased likelihood of having apositive response (i.e. an increased likelihood of having a negativeresponse) to treatment with a first RET inhibitor as a monotherapy. Alsoprovided are methods of determining the likelihood that a subject havinga cancer (e.g., a RET-associated cancer) will have a positive responseto treatment with a first RET inhibitor as a monotherapy that include:determining whether a cancer cell in a sample obtained from the subjecthas one or more RET inhibitor resistance mutations; and determining thata subject not having a cancer cell that has one or more RET inhibitorresistance mutations has an increased likelihood of having a positiveresponse to treatment with a first RET inhibitor as a monotherapy ascompared to a subject having a cancer cell that has one or more RETinhibitor resistance mutations. Also provided are methods of predictingthe efficacy of treatment with a first RET inhibitor as a monotherapy ina subject having cancer that include: determining whether a cancer cellin a sample obtained from the subject has one or more RET inhibitorresistance mutations; and determining that treatment with a first RETinhibitor as a monotherapy is less likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has oneor more RET inhibitor resistance mutations. Also provided are methods ofpredicting the efficacy of treatment with a first RET inhibitor as amonotherapy in a subject having cancer that include: determining thattreatment with a first RET inhibitor as a monotherapy is less likely tobe effective in a subject having a cancer cell in a sample obtained fromthe subject that has one or more RET inhibitor resistance mutations. Insome embodiments, the one or more RET inhibitor resistance mutationsconfer increased resistance to a cancer cell or tumor to treatment withthe first RET inhibitor. In some embodiments, the one or more RETinhibitor resistance mutations include one or more RET inhibitorresistance mutations listed in Tables 3 and 4. For example, the one ormore RET inhibitor resistance mutations can include a substitution atamino acid position 804, e.g., V804M, V804L, or V804E.

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a first RET inhibitor tothe subject for a period of time; (b) after (a), determining whether acancer cell in a sample obtained from the subject has at least one RETinhibitor resistance mutation; and (c) administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with another anticancer agent to thesubject if the subject has a cancer cell that has at least one RETinhibitor resistance mutation; or (d) administering additional doses ofthe first RET inhibitor of step (a) to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation. Insome embodiments, where the subject is administered additional doses ofthe first RET inhibitor of step (a), the subject can also beadministered another anticancer agent (e.g., a second RET inhibitor or acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or immunotherapy). In some embodiments, the additionalanticancer agent is any anticancer agent known in the art. For example,the additional anticancer agent is another RET inhibitor (e.g., a secondRET inhibitor). In some embodiments, the additional anticancer agent isan immunotherapy. In some embodiments of step (c), another RET inhibitorcan be the first RET inhibitor administered in step (a). In someembodiments, the one or more RET inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with thefirst RET inhibitor. In some embodiments, the one or more RET inhibitorresistance mutations include one or more RET inhibitor resistancemutations listed in Tables 3 and 4. For example, the one or more RETinhibitor resistance mutations can include a substitution at amino acidposition 804, e.g., V804M, V804L, or V804E.

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a first RET inhibitor tothe subject for a period of time; (b) after (a), determining whether acancer cell in a sample obtained from the subject has at least one RETinhibitor resistance mutation; and (c) administering a second RETinhibitor as a monotherapy or in conjunction with another anticanceragent to the subject if the subject has a cancer cell that has at leastone RET inhibitor resistance mutation; or (d) administering additionaldoses of the first RET inhibitor step (a) to the subject if the subjecthas a cancer cell that does not have a RET inhibitor resistancemutation. In some embodiments, where the subject is administeredadditional doses of the first RET inhibitor of step (a), the subject canalso be administered another anticancer agent. In some embodiments, theone or more RET inhibitor resistance mutations confer increasedresistance to a cancer cell or tumor to treatment with the first RETinhibitor. In some embodiments, the one or more RET inhibitor resistancemutations include one or more RET inhibitor resistance mutations listedin Tables 3 and 4. For example, the one or more RET inhibitor resistancemutations can include a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E. In some embodiments, the additional anticanceragent is any anticancer agent known in the art. For example, theadditional anticancer agent is another RET inhibitor (e.g., a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof).In some embodiments, the additional anticancer agent is animmunotherapy.

Also provided are methods of treating a subject having a cancer (e.g., aRET-associated cancer) that include: (a) determining whether a cancercell in a sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first RET inhibitor, has one or moreRET inhibitor resistance mutations; and (b) administering a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with another anticancer agent to thesubject if the subject has a cancer cell that has at least one RETinhibitor resistance mutation; or (c) administering additional doses ofthe first RET inhibitor previously administered to the subject if thesubject has cancer cell that does not have a RET inhibitor resistancemutation. In some embodiments, where the subject is administeredadditional doses of the first RET inhibitor previously administered tothe subject, the subject can also be administered another anticanceragent (e.g., a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof, or immunotherapy). In some embodiments, the oneor more RET inhibitor resistance mutations confer increased resistanceto a cancer cell or tumor to treatment with the first RET inhibitor. Insome embodiments, the one or more RET inhibitor resistance mutationsinclude one or more RET inhibitor resistance mutations listed in Tables3 and 4. For example, the one or more RET inhibitor resistance mutationscan include a substitution at amino acid position 804, e.g., V804M,V804L, or V804E. In some embodiments, the additional anticancer agent isany anticancer agent known in the art. For example, the additionalanticancer agent is another RET inhibitor (e.g., a second RETinhibitor). In some embodiments, the additional anticancer agent is animmunotherapy. In some embodiments of step (b), another anticancer agentcan be the first RET inhibitor administered in step (a).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a first RET inhibitor has one or more RET inhibitor resistancemutations; and (b) administering a second RET inhibitor as a monotherapyor in conjunction with another anticancer agent to the subject if thesubject has a cancer cell that has at least one RET inhibitor resistancemutation; or (c) administering additional doses of the first RETinhibitor previously administered to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation. Insome embodiments, where the subject is administered additional doses ofthe first RET inhibitor previously administered to the subject, thesubject can also be administered another anticancer agent. In someembodiments, the one or more RET inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with thefirst RET inhibitor. In some embodiments, the one or more RET inhibitorresistance mutations include one or more RET inhibitor resistancemutations listed in Tables 3 and 4. For example, the one or more RETinhibitor resistance mutations can include a substitution at amino acidposition 804, e.g., V804M, V804L, or V804E. In some embodiments, theadditional anticancer agent is any anticancer agent known in the art.For example, the additional anticancer agent is another RET inhibitor(e.g., a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof). In some embodiments, the additional anticancer agentis an immunotherapy. In some embodiments of (b), another anticanceragent can be the first RET inhibitor administered in step (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) administering one or more doses of a first RETinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one RET inhibitor resistance mutation; and (c) selecting acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with another anticancer agentfor the subject if the subject has a cancer cell that has one or moreRET inhibitor resistance mutations; or (d) selecting additional doses ofthe first RET inhibitor of step (a) for the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation. Insome embodiments, when additional doses of the first RET inhibitor ofstep (a) are selected for the subject, the method can further includeselecting doses of another anticancer agent for the subject. In someembodiments, the one or more RET inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with thefirst RET inhibitor. In some embodiments, the one or more RET inhibitorresistance mutations include one or more RET inhibitor resistancemutations listed in Tables 3 and 4. For example, the one or more RETinhibitor resistance mutations can include a substitution at amino acidposition 804, e.g., V804M, V804L, or V804E. In some embodiments, theadditional anticancer agent is any anticancer agent known in the art.For example, the additional anticancer agent is another RET inhibitor(e.g., a second RET inhibitor). In some embodiments, the additionalanticancer agent is an immunotherapy. In some embodiments of step (c),another RET inhibitor can be the first RET inhibitor administered instep (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) administering one or more doses of a first RETinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one RET inhibitor resistance mutation; and (c) selecting asecond RET inhibitor as a monotherapy or in conjunction with anotheranticancer agent if the subject has a cancer cell that has one or moreRET inhibitor resistance mutations; or (d) selecting additional doses ofthe first RET inhibitor of step (a) for the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation. Insome embodiments, when additional doses of the first RET inhibitor ofstep (a) are selected for the subject, the method can further includeselecting doses of another anticancer agent for the subject. In someembodiments, the one or more RET inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with thefirst RET inhibitor. In some embodiments, the one or more RET inhibitorresistance mutations include one or more RET inhibitor resistancemutations listed in Tables 3 and 4. For example, the one or more RETinhibitor resistance mutations can include a substitution at amino acidposition 804, e.g., V804M, V804L, or V804E. In some embodiments, theadditional anticancer agent is any anticancer agent known in the art.For example, the additional anticancer agent is another RET inhibitor(e.g., a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof). In some embodiments, the additional anticancer agentis an immunotherapy. In some embodiments, another RET can be the firstRET inhibitor administered in step (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) determining whether a cancer cell in a sampleobtained from a subject having a cancer and previously administered oneor more doses of a first RET inhibitor has one or more RET inhibitorresistance mutations; (b) selecting a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with another anticancer agent for the subject if thesubject has a cancer cell that has at least one RET inhibitor resistancemutation; or (c) selecting additional doses of the first RET inhibitorpreviously administered to the subject if the subject has a cancer cellthat does not have a RET inhibitor resistance mutation. In someembodiments, when additional doses of the first RET inhibitor previouslyadministered to the subject are selected for the subject, the method canfurther include selecting doses of another anticancer agent (e.g., acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or immunotherapy) for the subject. In some embodiments, the oneor more RET inhibitor resistance mutations confer increased resistanceto a cancer cell or tumor to treatment with the first RET inhibitor. Insome embodiments, the one or more RET inhibitor resistance mutationsinclude one or more RET inhibitor resistance mutations listed in Tables3 and 4. For example, the one or more RET inhibitor resistance mutationscan include a substitution at amino acid position 804, e.g., V804M,V804L, or V804E. In some embodiments, the additional anticancer agent isany anticancer agent known in the art. For example, the additionalanticancer agent is another RET inhibitor (e.g., a second RETinhibitor). In some embodiments, the additional anticancer agent is animmunotherapy. In some embodiments of step (c), another RET inhibitorcan be the first RET inhibitor administered in step (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) determining whether a cancer cell in a sampleobtained from a subject having a cancer and previously administered oneor more doses of a first RET inhibitor has one or more RET inhibitorresistance mutations; (b) selecting a second RET inhibitor as amonotherapy or in conjunction with another anticancer agent for thesubject if the subject has a cancer cell that has at least one RETinhibitor resistance mutation; or (c) selecting additional doses of thefirst RET inhibitor previously administered to the subject if thesubject has a cancer cell that does not have a RET inhibitor resistancemutation. In some embodiments, when additional doses of the first RETinhibitor previously administered to the subject are selected for thesubject, the method can further include selecting doses of anotheranticancer agent (e.g., a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or immunotherapy) for the subject.In some embodiments, the one or more RET inhibitor resistance mutationsconfer increased resistance to a cancer cell or tumor to treatment withthe first RET inhibitor. In some embodiments, the one or more RETinhibitor resistance mutations include one or more RET inhibitorresistance mutations listed in Tables 3 and 4. For example, the one ormore RET inhibitor resistance mutations can include a substitution atamino acid position 804, e.g., V804M, V804L, or V804E. In someembodiments, the additional anticancer agent is any anticancer agentknown in the art. For example, the additional anticancer agent isanother RET inhibitor (e.g., a compound of Formula I or apharmaceutically acceptable salt or solvate thereof). In someembodiments, the additional anticancer agent is an immunotherapy. Insome embodiments, another RET can be the first RET inhibitoradministered in step (a).

Also provided are methods of determining a subject's risk for developinga cancer that has some resistance to a first RET inhibitor that include:determining whether a cell in a sample obtained from the subject has oneor more RET inhibitor resistance mutations; and identifying a subjecthaving a cell that has one or more RET inhibitor resistance mutations,as having an increased likelihood of developing a cancer that has someresistance to the first RET inhibitor. Also provided are methods ofdetermining a subject's risk for developing a cancer that has someresistance to a first RET inhibitor that include: identifying a subjecthaving a cell that has one or more RET inhibitor resistance mutations,as having an increased likelihood of developing a cancer that has someresistance to the first RET inhibitor. Also provided are methods ofdetermining the presence of a cancer that has some resistance to a firstRET inhibitor that include: determining whether a cancer cell in asample obtained from the subject has one or more RET inhibitorresistance mutations; and determining that the subject having a cancercell that has one or more RET inhibitor resistance mutations has acancer that has some resistance to the first RET inhibitor. Alsoprovided are methods of determining the presence of a cancer that hassome resistance to a first RET inhibitor in a subject that include:determining that a subject having a cancer cell that has one or more RETinhibitor resistance mutations, has a cancer that has some resistance tothe first RET inhibitor. In some embodiments, the one or more RETinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with the first RET inhibitor. In someembodiments, the one or more RET inhibitor resistance mutations includeone or more RET inhibitor resistance mutations listed in Tables 3 and 4.For example, the one or more RET inhibitor resistance mutations caninclude a substitution at amino acid position 804, e.g., V804M, V804L,or V804E.

In some embodiments of any of the methods described herein, a RETinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with a first RET inhibitor can be anyof the RET inhibitor resistance mutations listed in Table 3 or 4 (e.g.,a substitution at amino acid position 804, e.g., V804M, V804L, orV804E).

In some embodiments, the presence of one or more RET inhibitorresistance mutations in a tumor causes the tumor to be more resistant totreatment with a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. Methods useful when a RET inhibitor resistancemutation causes the tumor to be more resistant to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof are described below. For example, provided herein are methods oftreating a subject having a cancer that include: identifying a subjecthaving a cancer cell that has one or more RET inhibitor resistancemutations; and administering to the identified subject a treatment thatdoes not include a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy (e.g., a second RETkinase inhibitor). Also provided are methods of treating a subjectidentified as having a cancer cell that has one or more RET inhibitorresistance mutations that include administering to the subject atreatment that does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy(e.g., a second RET kinase inhibitor). In some embodiments, the one ormore RET inhibitor resistance mutations confer increased resistance to acancer cell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided are methods of selecting a treatment for a subject havinga cancer that include: identifying a subject having a cancer cell thathas one or more RET inhibitor resistance mutations; and selecting atreatment that does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy forthe identified subject (e.g., a second RET kinase inhibitor). Alsoprovided are methods of selecting a treatment for a subject having acancer that include: selecting a treatment that does not include acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy (e.g., a second RET kinase inhibitor) for asubject identified as having a cancer cell that has one or more RETinhibitor resistance mutations. Also provided are methods of selecting asubject having a cancer for a treatment that does not include a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof asa monotherapy (e.g., a second RET kinase inhibitor) that include:identifying a subject having a cancer cell that has one or more RETinhibitor resistance mutations; and selecting the identified subject fora treatment that does not include a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy(e.g., a second RET kinase inhibitor). Also provided are methods ofselecting a subject having a cancer for a treatment that does notinclude a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy (e.g., a second RET kinase inhibitor)that include: selecting a subject identified as having a cancer cellthat has one or more RET inhibitor resistance mutations for a treatmentthat does not include a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy. In someembodiments, the one or more RET inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof.

Also provided are methods of determining the likelihood that a subjecthaving a cancer will have a positive response to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy that include: determining whether a cancer cellin a sample obtained from the subject has one or more RET inhibitorresistance mutations; and determining that the subject having the cancercell that has one or more RET inhibitor resistance mutations has adecreased likelihood of having a positive response to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy. Also provided are methods of determining thelikelihood that a subject having cancer will have a positive response totreatment with a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof as a monotherapy that include: determining thata subject having a cancer cell that has one or more RET inhibitorresistance mutations has a decreased likelihood of having a positiveresponse to treatment with a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy. Also provided aremethods of predicting the efficacy of treatment with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy in a subject having cancer that include: determining whethera cancer cell in a sample obtained from the subject has one or more RETinhibitor resistance mutations; and determining that treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy is less likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has oneor more RET inhibitor resistance mutations. Also provided are methods ofpredicting the efficacy of treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy ina subject having cancer that include: determining that treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy is less likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has oneor more RET inhibitor resistance mutations. In some embodiments, the oneor more RET inhibitor resistance mutations confer increased resistanceto a cancer cell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof for a period oftime; (b) after (a), determining whether a cancer cell in a sampleobtained from the subject has one or more RET inhibitor resistancemutations; and (c) administering a second RET inhibitor or a secondcompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with another anticancer agentto a subject having a cancer cell that has one or more RET inhibitorresistance mutations; or (d) administering additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof of step (a) to a subject having a cancer cell that does not havea RET inhibitor resistance mutation. In some embodiments, where thesubject is administered additional doses of the compound of Formula I ora pharmaceutically acceptable salt or solvate thereof of step (a), thesubject can also be administered another anticancer agent or a secondcompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the one or more RET inhibitor resistancemutations confer increased resistance to a cancer cell or tumor totreatment with a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the additional anticanceragent is any anticancer agent known in the art. For example, theadditional anticancer agent is another RET inhibitor (e.g., a second RETinhibitor). In some embodiments, the additional anticancer agent is animmunotherapy. In some embodiments, another RET can be the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofadministered in step (a).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, has one or more RET inhibitor resistance mutations; (b)administering a second RET inhibitor or a second compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with another anticancer agent to a subjecthaving a cancer cell that has one or more RET inhibitor resistancemutations; or (c) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofpreviously administered to a subject having a cancer cell that does nothave a RET inhibitor resistance mutation. In some embodiments, where thesubject is administered additional doses of the compound of Formula I ora pharmaceutically acceptable salt or solvate thereof of step (a), thesubject can also be administered another anticancer agent. In someembodiments, the one or more RET inhibitor resistance mutations conferincreased resistance to a cancer cell or tumor to treatment with acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the additional anticancer agent is anyanticancer agent known in the art. For example, the additionalanticancer agent is another RET inhibitor (e.g., a second RETinhibitor). In some embodiments, the additional anticancer agent is animmunotherapy. In some embodiments, another RET can be the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereofadministered in step (a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include: (a) administering one or more doses of a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof tothe subject for a period of time; (b) after (a), determining whether acancer cell in a sample obtained from the subject has one or more RETinhibitor resistance mutations; and (c) selecting a second RET inhibitoror a second compound of Formula I or a pharmaceutically acceptable saltor solvate thereof as a monotherapy or in conjunction with anotheranticancer agent for the subject if the subject has a cancer cell thathas a RET inhibitor resistance mutation; or (d) selecting additionaldoses of the compound of Formula I or a pharmaceutically acceptable saltor solvate thereof of step (a) for the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation. Insome embodiments, where additional doses of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof of step (a) areselected for the subject, the method can also include further selectinganother anticancer agent. In some embodiments, the one or more RETinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the additional anticancer agent is any anticancer agentknown in the art. For example, the additional anticancer agent isanother RET inhibitor (e.g., a second RET inhibitor). In someembodiments, the additional anticancer agent is an immunotherapy. Insome embodiments, another RET can be the compound of Formula I or apharmaceutically acceptable salt or solvate thereof administered in step(a).

Also provided are methods of selecting a treatment for a subject havinga cancer that include: (a) determining whether a cancer cell in a sampleobtained from a subject having a cancer and previously administered oneor more doses of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, has one or more RET inhibitorresistance mutations; (b) selecting a second RET inhibitor or a secondcompound of Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy or in conjunction with another anticancer agentfor the subject if the subject has a cancer cell that has a RETinhibitor resistance mutation; or (c) selecting additional doses of thecompound of Formula I or a pharmaceutically acceptable salt or solvatethereof previously administered to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation. Insome embodiments, where additional doses of the compound of Formula I ora pharmaceutically acceptable salt or solvate thereof of step (a) areselected for the subject, the method can also include further selectinganother anticancer agent. In some embodiments, the one or more RETinhibitor resistance mutations confer increased resistance to a cancercell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the additional anticancer agent is any anticancer agentknown in the art. For example, the additional anticancer agent isanother RET inhibitor (e.g., a second RET inhibitor). In someembodiments, the additional anticancer agent is an immunotherapy. Insome embodiments, another RET can be the compound of Formula I or apharmaceutically acceptable salt or solvate thereof administered in step(a).

Also provided are methods of determining a subject's risk for developinga cancer that has some resistance to a compound of Formula I or apharmaceutically acceptable salt or solvate thereof that include:determining whether a cell in a sample obtained from the subject has oneor more RET inhibitor resistance mutations; and identifying the subjectif the subject has a cell that has one or more RET inhibitor resistancemutations as having an increased likelihood of developing a cancer thathas some resistance to a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof. Also provided are methods ofdetermining a subject's risk for developing a cancer that has someresistance to a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof that include: identifying a subject having acell that has one or more RET inhibitor resistance mutations as havingan increased likelihood of developing a cancer that has some resistanceto a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof. Also provided are methods of determining the presenceof a cancer that has some resistance to a compound of Formula I or apharmaceutically acceptable salt or solvate thereof that includes:determining whether a cancer cell in a sample obtained from the subjecthas one or more RET inhibitor resistance mutations; and determining thatthe subject having the cancer cell that has one or more RET inhibitorresistance mutations has a cancer that has some resistance to a compoundof Formula I or a pharmaceutically acceptable salt or solvate thereof.Also provided are methods of determining the presence of a cancer thathas some resistance to a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof in a subject that include:determining that a subject having a cancer cell that has one or more RETinhibitor resistance mutations has a cancer that has some resistance toa compound of Formula I or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the one or more RET inhibitor resistancemutations confer increased resistance to a cancer cell or tumor totreatment with a compound of Formula I or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments of any of the methods described herein, a RETinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, can be any of theRET inhibitor resistance mutations listed in Table 3 or 4.

Methods of determining the level of resistance of a cancer cell or atumor to a RET inhibitor (e.g., any of the RET inhibitors describedherein or known in the art) can be determined using methods known in theart. For example, the level of resistance of a cancer cell to a RETinhibitor can be assessed by determining the IC₅₀ of a RET inhibitor(e.g., any of the RET inhibitors described herein or known in the art)on the viability of a cancer cell. In other examples, the level ofresistance of a cancer cell to a RET inhibitor can be assessed bydetermining the growth rate of the cancer cell in the presence of a RETinhibitor (e.g., any of the RET inhibitors described herein). In otherexamples, the level of resistance of a tumor to a RET inhibitor can beassessed by determining the mass or size of one or more tumors in asubject over time during treatment with a RET inhibitor (e.g., any ofthe RET inhibitors described herein). In other examples, the level ofresistance of a cancer cell or a tumor to a RET inhibitor can beindirectly assessed by determining the activity of a RET kinaseincluding one or more of the RET inhibitor resistance mutations (i.e.,the same RET kinase expressed in a cancer cell or a tumor in a subject).The level of resistance of a cancer cell or tumor having one or more RETinhibitor resistance mutations to a RET inhibitor is relative to thelevel of resistance in a cancer cell or tumor that does not have a RETinhibitor resistance mutation (e.g., a cancer cell or tumor that doesnot have the same RET inhibitor resistance mutations, a cancer cell or atumor that does not have any RET inhibitor resistance mutations, or acancer cell or a tumor that expresses a wildtype RET protein). Forexample, the determined level of resistance of a cancer cell or a tumorhaving one or more RET inhibitor resistance mutations can be greaterthan about 1%, greater than about 2%, greater than about 3%, greaterthan about 4%, greater than about 5%, greater than about 6%, greaterthan about 7%, greater than about 8%, greater than about 9%, greaterthan about 10%, greater than about 11%, greater than about 12%, greaterthan about 13%, greater than about 14%, greater than about 15%, greaterthan about 20%, greater than about 25%, greater than about 30%, greaterthan about 35%, greater than about 40%, greater than about 45%, greaterthan about 50%, greater than about 60%, greater than about 70%, greaterthan about 80%, greater than about 90%, greater than about 100%, greaterthan about 110%, greater than about 120%, greater than about 130%,greater than about 140%, greater than about 150%, greater than about160%, greater than about 170%, greater than about 180%, greater thanabout 190%, greater than about 200%, greater than about 210%, greaterthan about 220%, greater than about 230%, greater than about 240%,greater than about 250%, greater than about 260%, greater than about270%, greater than about 280%, greater than about 290%, or greater thanabout 300% of the level of resistance in a cancer cell or tumor thatdoes not have a RET inhibitor resistance mutation (e.g., a cancer cellor tumor that does not have the same RET inhibitor resistance mutations,a cancer cell or a tumor that does not have any RET inhibitor resistancemutations, or a cancer cell or a tumor that expresses a wildtype RETprotein).

RET is thought to play an important role in the development and survivalof afferent nociceptors in the skin and gut. RET kinase knock-out micelack enteric neurons and have other nervous system anomalies suggestingthat a functional RET kinase protein product is necessary duringdevelopment (Taraviras, S. et al., Development, 1999, 126:2785-2797).Moreover population studies of patients with Hirschsprung's diseasecharacterized by colonic obstruction due to lack of normal colonicenervation have a higher proportion of both familial and sporadic lossof function RET mutations (Butler Tjaden N., et al., Transl. Res., 2013,162: 1-15). Irritable bowel syndrome (IBS) is a common illness affecting10-20% of individuals in developed countries and is characterized byabnormal bowel habits, bloating and visceral hypersensitivity(Camilleri, M., N. Engl. J. Med., 2012, 367: 1626-1635). While theetiology of IBS is unknown it is thought to result from either adisorder between the brain and gastrointestinal tract, a disturbance inthe gut microbiome or increased inflammation. The resultinggastrointestinal changes affect normal bowel transit resulting in eitherdiarrhea or constipation. Furthermore in many IBS patients thesensitization of the peripheral nervous system results in visceralhypersensitivity or allodynia (Keszthelyi, D., Eur. J. Pain, 2012, 16:1444-1454). See, e.g., U.S. Publication No. 2015/0099762.

Accordingly, provided herein are methods for treating a patientdiagnosed with (or identified as having) an irritable bowel syndrome(IBS) including diarrhea-predominant, constipation- predominant oralternating stool pattern, functional bloating, functional constipation,functional diarrhea, unspecified functional bowel disorder, functionalabdominal pain syndrome, chronic idiopathic constipation, functionalesophageal disorders, functional gastroduodenal disorders, functionalanorectal pain, and inflammatory bowel disease that includeadministering to the patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof.

Also provided herein are methods for treating a patient identified ordiagnosed as having a RET-associated irritable bowel syndrome (IBS)(e.g., a patient that has been identified or diagnosed as having aRET-associated irritable bowel syndrome (IBS) through the use of aregulatory agency-approved, e.g., FDA-approved, kit for identifyingdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, in a patient or a biopsy sample from thepatient) that include administering to the patient a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof.

Also provided herein are methods for treating pain associated with IBSthat include administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, a compound of Formula I or apharmaceutically acceptable salt or solvate thereof is administered incombination with another therapeutic agent useful for treating one ormore symptoms of IBS.

Also provided are methods for treating an irritable bowel syndrome (IBS)in a patient in need thereof, the method comprising: (a) determining ifthe irritable bowel syndrome (IBS) in the patient is a RET-associatedIBS (e.g., using a regulatory-agency approved, e.g., FDA-approved, kitfor identifying dysregulation of a RET gene, a RET kinase, or expressionor activity or level of any of the same, in a patient or a biopsy samplefrom the patient, or by performing any of the non-limiting examples ofassays described herein); and (b) if the IBS is determined to be aRET-associated IBS, administering to the patient a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof.

In some embodiments, the compounds of the present invention are usefulfor treating irritable bowel syndrome (IBS) in combination with one ormore additional therapeutic agents or therapies effective in treatingthe irritable bowel syndrome that work by the same or a differentmechanism of action. The at least one additional therapeutic agent maybe administered with a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof as part of the same or separatedosage forms, via the same or different routes of administration, and onthe same or different administration schedules according to standardpharmaceutical practice known to one skilled in the art.

Non-limiting examples of additional therapeutics for the treatment ofirritable bowel syndrome (IBS) include probiotics, fiber supplements(e.g., psyllium, methylcellulose), anti-diarrheal medications (e.g.,loperamide), bile acid binders (e.g., cholestyramine, colestipol,colesevelam), anticholinergic and antispasmodic medications (e.g.,hyoscyamine, dicyclomine), antidepressant medications (e.g., tricyclicantidepressant such as imipramine or notriptyline or a selectiveserotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine),antibiotics (e.g., rifaximin), alosetron, and lubiprostone.

Accordingly, also provided herein are methods of treating irritablebowel syndrome (IBS), comprising administering to a patient in needthereof a pharmaceutical combination for treating IBS which comprises(a) a compound of Formula I or pharmaceutically acceptable salt orsolvate thereof, (b) an additional therapeutic agent, and (c) optionallyat least one pharmaceutically acceptable carrier for simultaneous,separate or sequential use for the treatment of IBS, wherein the amountsof the compound of Formula I or pharmaceutically acceptable salt orsolvate thereof and the additional therapeutic agent are togethereffective in treating the IBS. In one embodiment, the compound ofFormula I or pharmaceutically acceptable salt or solvate thereof, andthe additional therapeutic agent are administered simultaneously asseparate dosages. In one embodiment, the compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered as separate dosages sequentially inany order, in jointly therapeutically effective amounts, e.g. in dailyor intermittently dosages. In one embodiment, compound of Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as a combined dosage.

Also provided herein is (i) a pharmaceutical combination for treatingirritable bowel syndrome in a patient in need thereof, which comprises(a) a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, (b) at least one additional therapeutic agent (e.g.,any of the exemplary additional therapeutic agents described herein fortreating irritable bowel syndrome or known in the art), and (c)optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of irritablebowel syndrome, wherein the amounts of the compound of Formula I orpharmaceutically acceptable salt or solvate thereof and of theadditional therapeutic agent are together effective in treating theirritable bowel syndrome; (ii) a pharmaceutical composition comprisingsuch a combination; (iii) the use of such a combination for thepreparation of a medicament for the treatment of irritable bowelsyndrome; and (iv) a commercial package or product comprising such acombination as a combined preparation for simultaneous, separate orsequential use; and to a method of treatment of irritable bowel syndromein a patient in need thereof. In one embodiment the patient is a human.

The term “pharmaceutical combination”, as used herein, refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof and at least one additional therapeutic agent (e.g.,an agent effective in treating irritable bowel syndrome), are bothadministered to a patient simultaneously in the form of a singlecomposition or dosage. The term “non-fixed combination” means that acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof and at least one additional therapeutic agent (e.g., an agenteffective in treating irritable bowel syndrome) are formulated asseparate compositions or dosages, such that they may be administered toa patient in need thereof simultaneously, concurrently or sequentiallywith variable intervening time limits, wherein such administrationprovides effective levels of the two or more compounds in the body ofthe patient. In one embodiment, the compound of Formula I and theadditional therapeutic agent are formulated as separate unit dosageforms, wherein the separate dosages forms are suitable for eithersequential or simultaneous administration. These also apply to cocktailtherapies, e.g. the administration of three or more active ingredients.

In some embodiments, a compound provided herein can be used as an agentfor supportive care for a patient undergoing cancer treatment. Forexample, a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof, can be useful to reduce one or more symptomsassociated with treatment with one or more cancer therapies such asdiarrheal or constipations complications and/or abdominal pain. See, forexample, U.S. Publication No. 2015/0099762 and Hoffman, J. M. et al.Gastroenterology (2012) 142:844-854. Accordingly, a compound, or apharmaceutically acceptable salt thereof, or composition provided hereincan be administered to a patient to address one or more complicationsassociated with cancer treatment (e.g., gastrointestinal complicationssuch as diarrhea, constipation, or abdominal pain).

In some embodiments, a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, canbe administered to a patient undergoing cancer treatment (e.g., apatient experiencing an adverse event associated with cancer treatmentsuch as an immune-related adverse event or a gastrointestinalcomplication including diarrhea, constipation, and abdominal pain). Forexample, a compound provided herein, or a pharmaceutically acceptablesalt thereof, can be used in the treatment of colitis or IBS associatedwith administration of a checkpoint inhibitor; see, e.g., Postow, M. A.et al. Journal of Clinical Oncology (2015) 33: 1974-1982. In some suchembodiments, a compound provided herein, or a pharmaceuticallyacceptable salt thereof, can be formulated to exhibit lowbioavailability and/or be targeted for delivery in the gastrointestinaltract. See, for example, U.S. Pat. No. 6,531,152.

Also provided is a method for inhibiting RET kinase activity in a cell,comprising contacting the cell with a compound of Formula I. In oneembodiment, the contacting is in vitro. In one embodiment, thecontacting is in vivo. In one embodiment, the contacting is in vivo,wherein the method comprises administering an effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof to a subject having a cell having RET kinase activity. In someembodiments, the cell is a cancer cell. In one embodiment, the cancercell is any cancer as described herein. In some embodiments, the cancercell is a RET-associated cancer cell. In some embodiments, the cell is agastrointestinal cell.

Also provided is a method for inhibiting RET kinase activity in amammalian cell, comprising contacting the cell with a compound ofFormula I. In one embodiment, the contacting is in vitro. In oneembodiment, the contacting is in vivo. In one embodiment, the contactingis in vivo, wherein the method comprises administering an effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltor solvate thereof to a mammal having a cell having RET kinase activity.In some embodiments, the mammalian cell is a mammalian cancer cell. Inone embodiment, the mammalian cancer cell is any cancer as describedherein. In some embodiments, the mammalian cancer cell is aRET-associated cancer cell. In some embodiments, the mammalian cell is agastrointestinal cell.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a RET kinase with a compound provided hereinincludes the administration of a compound provided herein to anindividual or patient, such as a human, having a RET kinase, as well as,for example, introducing a compound provided herein into a samplecontaining a cellular or purified preparation containing the RET kinase.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositionthereof as defined herein

The phrase “effective amount” means an amount of compound that, whenadministered to a patient in need of such treatment, is sufficient to(i) treat a RET kinase-associated disease or disorder, (ii) attenuate,ameliorate, or eliminate one or more symptoms of the particular disease,condition, or disorder, or (iii) delay the onset of one or more symptomsof the particular disease, condition, or disorder described herein. Theamount of a compound of Formula I that will correspond to such an amountwill vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of thepatient in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

When employed as pharmaceuticals, the compounds of Formula I can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Oral administrationcan include a dosage form formulated for once-daily or twice-daily (BID)administration. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal intramuscular or injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable

Also provided herein are pharmaceutical compositions which contain, asthe active ingredient, a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, in combination with one or morepharmaceutically acceptable carriers (excipients). In some embodiments,the composition is suitable for topical administration. In making thecompositions provided herein, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders. In oneembodiment, the composition is formulated for oral administration. Inone embodiment, the composition is formulated as a tablet or capsule.

The compositions comprising a compound of Formula I or apharmaceutically acceptable salt or solvate thereof can be formulated ina unit dosage form, each dosage containing from about 5 to about 1,000mg (1 g), more usually about 100 mg to about 500 mg, of the activeingredient. The term “unit dosage form” refers to physically discreteunits suitable as unitary dosages for human subjects and other patients,each unit containing a predetermined quantity of active material (i.e.,a compound for Formula I as provided herein) calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

In some embodiments, the compositions provided herein contain from about5 mg to about 50 mg of the active ingredient. One having ordinary skillin the art will appreciate that this embodies compounds or compositionscontaining about 5 mg to about 10 mg, about 10 mg to about 15 mg, about15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40mg to about 45 mg, or about 45 mg to about 50 mg of the activeingredient.

In some embodiments, the compositions provided herein contain from about50 mg to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 50 mg to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about450 mg to about 500 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about500 mg to about 1,000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 500 mg to about 550 mg, about 550 mg toabout 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg toabout 950 mg, or about 950 mg to about 1,000 mg of the activeingredient.

In some embodiments, the compounds provided herein can be administeredin an amount ranging from about 1 mg/kg to about 100 mg/kg. In someembodiments, the compound provided herein can be administered in anamount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70mg/kg. For example, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg,about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg. In someembodiments, such administration can be once-daily or twice-daily (BID)administration.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

Provided herein are pharmaceutical kits useful, for example, in thetreatment of RET-associated diseases or disorders, such as cancer orirritable bowel syndrome (IBS), which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound provided herein. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

EXAMPLES

The following examples illustrate the invention.

BIOLOGICAL EXAMPLES Example A RET Enzyme Assay

Compounds of Formula I were screened for their ability to inhibitwildtype and V804M mutant RET kinase using CisBio's HTRF® KinEASE™-TKassay technology. Briefly, N-terminal GST tagged recombinant human RETcytoplasmic domain (aa 658-end) from Eurofins (0.25 nM RET; Catalog No.14-570M) or N-terminal GST tagged recombinant human V804M mutant RETcytoplasmic domain (aa 658-end) from Millipore (0.25 nM enzyme; CatalogNo. 14-760) was incubated with 250 nM TK-substrate biotin (CisBio, partof Catalog No. 62TKOPEC) and 1 mM ATP along with test compound in abuffer consisting of 25 mM HEPES pH 7.4, 10 mM MgCl₂, 0.01% TritonX-100, and 2% DMSO in a volume of 8 μL. Compounds were typicallyprepared in a threefold serial dilution in DMSO and added to the assayto give the appropriate final concentration. After a 30-minuteincubation at 22° C., the reaction was quenched by adding 8 μL of quenchsolution containing 31.25 nM Sa-XL665 and 1×TK-ab-Cryptate in HTRFdetection buffer (all from CisBio, part of Cat. No. 62TKOPEC). After a 1hour incubation at 22° C., the extent of reaction was determined using aPerkinElmer EnVision multimode plate reader via HTRF dual wavelengthdetection, and the percent of control (POC) was calculated using aratiometric emission factor. 100 POC was determined using no testcompounds and 0 POC was determined using pre-quenched control reactions.The POC values were fit to a 4 parameter logistic curve, and the IC₅₀ isdefined as the concentration of inhibitor at which the POC equals 50 forthe fitted curve. The IC₅₀ values for the compounds tested in this assayare provided in Table 5.

Example B

RET Cell Assay

The cellular potency of a compound inhibiting RET kinase was determinedin HEK-293 cells expressing a Kif5b-RET fusion protein. Briefly, HEK-293cells expressing a Kif5b-RET fusion protein were plated at 50Kcells/well in 96 well poly-D-Lysine coated plates the day prior to theassay. The cells were incubated for 1 hour with test compound in DMEM(Dulbecco's Modified Eagle Medium) at a final DMSO concentration of0.5%. Compounds were typically prepared in a three fold serial dilutionin DMSO and added to the assay to give the appropriate finalconcentration. After 1 hour the media was removed, the cells were fixedwith 3.8% formaldehyde for 20 min, washed with PBS, and permeabilizedfor 10 min with 100% methanol. The plates were then washed withPBS-0.05% Tween20, and blocked with LI-COR Blocking solution (LI-CORcatalog #927-40000) for 1 hour. Plates were washed with PBS-0.05%Tween20, then incubated with anti-phospho-RET(Tyr1062) (Santa Cruzcatalog #sc-20252-R) antibody and anti-GAPDH (Millipore catalog #MAB374)antibody for 2 hours. The plates were washed with PBS-0.05% Tween20, andincubated with anti-rabbit 680 (Molecular Probes catalog No. A21109) andanti-mouse 800 (LI-COR catalog No. 926-32210) secondary antibodies for 1hour. All antibodies were diluted in LI-COR Block containing 0.05%Tween. The plates were washed with PBS-0.05% Tween20, 100 μL PBS wasadded to each well, and the plates were read on a LI-COR Aeriusfluorescent plate reader. The phospho-RET signal was normalized to theGAPDH signal. 100 POC (percent of control) was determined using no testcompounds and 0 POC was determined using 1 μM of a control inhibitor.The POC values were fit to a 4 parameter logistic curve. The IC₅₀ valueis the point where the curve crosses 50 POC. The IC₅₀ values for thecompounds tested in this assay are provided in Table 5.

Example C

RET G810R Mutant Assay

The potency of a compound inhibiting G81 OR mutant RET kinase wasdetermined using CisBio's HTRF Kinease-TK assay technology. The assayscontained G81OR mutant RET produced at Array Biopharma, Inc. (1 nMenzyme—p1982 Lot. No. 160713. The kinase was incubated with 250 nMTK-substrate biotin (CisBio, part of Catalog #62TKOPEC) and 1 mM ATPalong with test compound in a buffer consisting of 25 mM HEPES, pH 7.4,10 mM MgCl₂, 0.01% Triton X-100, and 2% DMSO in a volume of 8 μL.Compounds were typically prepared as a three-fold serial dilution inDMSO and added to the assay to give the appropriate final concentration.After a 60-min incubation at 22° C., the reaction was quenched by adding8 μL of quench solution containing 31.25 nM Sa-XL665 and1×TK-Ab-Cryptate in HTRF detection buffer (all from CisBio, part of cat#62TKOPEC). After a 1-h incubation at 22° C., the extent of reaction wasdetermined using a PerkinElmer EnVision multimode plate reader via HTRFdual wavelength detection, and the percent of control (POC) wascalculated using a ratiometric emission factor. One hundred POC wasdetermined using no test compounds, and 0 POC was determined usingpre-quenched control reactions. A 4-parameter logistic curve was fit tothe POC values as a function of the concentration of compound, and theIC₅₀ value was the point where the best-fit curve crossed 50 POC.

TABLE 5 IC₅₀'s of compounds tested in the assay of Examples A, B and CRET Enzyme RET enzyme KIF5B-RET RET Enzyme (wild type) (V804M) pTYR1062(G810R) IC₅₀ IC₅₀ Cell IC₅₀ IC50 Ex. # (nM) (nM) (nM) (nM) 1 91.5 758.2205.6 1026 2 1891.7 3930.6 N/A N/A 3 82.9 587.7 143 N/A 4 231.4 1969.1N/A N/A 5 457.3 3808.5 N/A 3669 6 1518.4 N/A N/A N/A 7 105.5 1107.7 364N/A 8 41.5 285.3 146.2 N/A 9 18.8 24.6 9.8 128 10 61.2 264.4 163.8 N/A11 93.6 511.3 722.8 N/A 12 34.8 328.3 212.8 N/A 13 23.1 127.2 54.8 N/A14 199.1 817.4 N/A N/A 15 264.6 1038.8 N/A N/A 16 69.9 199.1 61.1 N/A 17165.4 1874.7 N/A N/A 18 54.7 632.3 366.1 N/A 19 24.6 120.1 20.6 N/A 20336.9 1571.7 N/A N/A 21 15.5 70.6 25.5 N/A 22 16.6 138.1 38 N/A 23 15.683.9 43.3 N/A 24 49 355 310 N/A 25 38.1 207.5 330 N/A 26 40.6 183.2165.6 N/A 27 15.3 50.4 8.3 636 28 158 1020.9 N/A N/A 29 15.5 54.6 8.4613 30 49.6 236.4 41.1 N/A 31 75.8 316.4 137.9 N/A 32 90.2 502.2 97.8N/A 33 44.5 215.2 20.8 N/A 34 64.9 402.2 72.2 N/A 35 8.4 17.3 2.7 133 368 20.2 6.3 N/A 37 16 39.3 4.7 N/A 38 13.3 22 3.6 N/A 39 17.2 54.3 12.7550 40 18.5 70 16.8 632 41 80.2 248.9 48 N/A 42 6.7 13.6 1.5 N/A 43 12.221 5.4 N/A 44 20.7 108.2 31.6 195 45 6.3 20.9 2.9 37 46 14.5 44.5 11.2N/A 47 13.7 34.8 4.2 64 48 10 17.3 2.5 N/A 49 29.6 169 34.6 1375 50 67.8585.6 135.5 N/A 51 112.7 442.8 N/A N/A 52 20.1 49.7 2 N/A 53 14.4 27.91.3 N/A 54 10.8 21.1 1.2 N/A 55 22.9 70.7 3.4 N/A 56 13.9 35.9 1.2 N/A57 14.8 94.5 12.5 N/A 58 68.6 692.1 153.1 N/A 59 74.3 401.5 170.7 N/A 6050.5 194.2 93 N/A 61 22.4 97.5 17.8 N/A 62 13.4 31.9 1.7 92 63 66.5511.9 150.1 N/A 64 19.2 69 10 628 65 9.1 45.7 6.1 N/A 66 9.1 27.5 1.5N/A 67 21.6 49.9 11.4 N/A 68 19 64.8 13.3 N/A 69 14.9 49.7 11.7 N/A 7016.4 46.4 10.1 N/A 71 74.6 586.8 80 N/A 72 14.7 46.2 2 N/A 73 16.3 49.11.9 N/A 74 11.5 57.4 10.3 N/A 75 24.6 50.2 4.7 N/A 76 23.9 77.6 54.9 N/A77 16.5 33.3 3 N/A 78 25 34.5 2 280 79 43.3 105.7 6.3 755 80 13.9 25.9 2N/A 81 11.2 27 2.6 N/A 82 61.3 250.6 58.5 N/A 83 34.2 79.6 6.8 1711 8425.5 128.8 45.6 N/A 85 39.8 150.8 91.3 N/A 86 16.7 72.5 20 N/A 87 5.330.7 9.7 463 88 26.2 71 4.2 N/A 89 26.9 282.8 38.7 N/A 90 29.3 153.930.8 N/A 91 13.3 52.7 7.9 N/A 92 11.3 40.3 6.4 N/A 93 9.4 19 1.8 N/A 9416.8 28.8 3.7 N/A 95 79.9 478.5 1667 N/A 96 48.9 311.9 689.8 N/A 97137.5 602.4 N/A N/A 98 208.9 1549.4 N/A N/A 99 21.1 100.7 265.2 N/A 10038 100.5 10.6 N/A 101 12.8 29.7 1.2 N/A 102 11.8 27.5 1 N/A 103 61.8323.2 57.7 N/A 104 10.7 20.4 3.1 N/A 105 11.2 25 1.2 96 106 24.7 90.312.2 N/A 107 12.4 51.6 9.4 N/A 108 12.6 73.9 5.6 N/A 109 18.3 65.2 30N/A 110 22.6 42.8 44.4 N/A 111 25.3 255.8 40 N/A 112 40.4 243.5 48.5 N/A113 70.5 237.4 168.4 N/A 114 65.6 106.8 37.4 N/A 115 155.9 321.8 N/A N/A116 86.9 578 136.1 N/A 117 46.2 160 39.1 N/A 118 49.8 352.6 51 N/A 11969.9 119.7 34.9 N/A 120 177.4 846.1 N/A N/A 121 276.1 1622.5 N/A N/A 122124.3 580.7 N/A N/A 123 51.1 123.4 73.6 N/A 124 31.3 104.4 8.9 N/A 12524.1 134.3 32.7 N/A 126 222.4 1516.6 N/A N/A 127 43.2 191.1 26.5 N/A 12894.8 584.7 113.7 N/A 129 21.7 37.8 3.2 N/A 130 21 40.5 3.5 N/A 131 2140.7 3.5 N/A 132 24.8 68.4 7.6 N/A 133 16 31.1 2.4 N/A 134 34.5 187.968.2 N/A 135 22.1 151.2 41.8 N/A 136 31.9 196.3 130.5 N/A 137 30.3 242.4226.8 N/A 138 164.5 1108.6 N/A N/A 139 12.4 22.8 1.4 N/A 140 7.9 47 9.2N/A 141 48.1 346.6 115.6 N/A 142 56 405.5 169.2 N/A 143 50.1 310.5 377.3N/A 144 9.8 22.2 1.1 N/A 145 32.3 118.3 9.1 N/A 146 19.1 47.6 1.6 N/A147 18.5 44.7 5.6 N/A 148 102.7 1153.6 N/A N/A 149 131.8 1076.2 N/A N/A150 133.2 1117.3 N/A N/A 151 39.5 129.6 77.2 N/A 152 49.9 163.6 106 N/A153 230.6 2403.5 N/A N/A 154 142.6 962.4 N/A N/A 155 21.3 97.2 44.1 N/A156 28.4 108 31 N/A 157 21.3 47.2 10.2 N/A 158 1716.6 10000 N/A N/A 15925.3 181.2 49.7 N/A 160 91 512.3 294.2 N/A 161 8.7 19.2 6.1 N/A 162 17.445.7 9.8 N/A 163 28.8 104.4 34.9 N/A 164 358.2 4281.1 N/A N/A 165 14.660.1 37.6 N/A 166 1023.9 10000 N/A N/A 167 16.7 39.3 9.2 N/A 168 5.814.6 5.2 N/A 169 8.2 35.3 13.7 N/A 170 44.3 260.8 162.6 N/A 171 29.3134.2 89.7 N/A 172 338.7 3403.3 N/A N/A 173 1976.5 10000 N/A N/A 174 9.817.8 3.2 N/A 175 75.8 417.4 272.4 N/A 176 26.4 77.5 18.4 N/A 177 20.9 4613.3 N/A 178 73.2 429.1 354.2 N/A 179 27.1 139 59.6 N/A 180 68.6 328.6362.8 N/A 181 83.6 478 78.6 N/A 182 191.5 1299.6 N/A N/A 183 15.4 41.223.4 N/A 184 40 379.3 271 N/A 185 10.4 93.9 50 N/A 186 15.5 68.9 25.4N/A 187 5 15.2 8.3 N/A 188 13.7 75.5 44.6 N/A 189 9.2 35 36.7 N/A 19022.4 201.9 39.1 N/A 191 93.7 1197.3 968.7 N/A 192 12.9 50.5 27.3 N/A 19321.1 73.8 26.2 N/A 194 70.3 585.5 165.6 N/A 195 124.6 1864.5 N/A N/A 19616 200.5 29.5 N/A 197 45.3 316.2 179.3 N/A 198 18.3 126.7 61.7 N/A 19914.7 107.5 40.3 N/A 200 554.4 4088.7 N/A N/A 201 10.5 22.7 4.5 165 20211.6 26.5 18.9 181 203 9.2 68.3 23.3 N/A 204 82.3 813.1 N/A 495 205 10.762.1 6.5 275 206 13.8 91.1 44.2 N/A 207 18 92.7 27 496 208 20 87.2 23.9N/A 209 11 141.8 36.3 N/A 210 19.7 272.8 94.7 1600 211 84 767.9 445.18099 212 19.2 69.4 12 286 213 16.3 137.4 34.3 N/A 214 21.4 38.4 14.2 N/A215 30.2 272 110.6 N/A 216 195.9 1574.7 N/A N/A 217 7.9 45.3 15.5 N/A218 25.3 222 69.5 N/A 219 17.3 109.2 43.9 N/A 220 33 229.7 57.2 N/A 22110.9 49.9 16.3 N/A 222 22.2 59.5 6.3 N/A 223 193.6 1614.9 N/A N/A 22414.4 84.5 14.5 N/A 225 39.1 316.7 141.6 N/A 226 16.9 152.4 20.9 N/A 22718 140.5 26.5 N/A 228 33.5 411.4 64.8 N/A 229 10.3 213.5 140.45 N/A 230251.3 3206.5 N/A N/A 231 12.8 56.9 7.6 N/A 232 22.1 122.9 127.3 N/A 23310.5 44 5.3 N/A 234 15.1 49.8 5.2 N/A 235 26.9 155 32.1 N/A 236 30.3132.7 22.4 N/A 237 23.9 74.7 12.6 1169 238 99 573.7 260.9 N/A 239 11.933.8 4.6 253 240 15.4 51 4.5 245 241 21.7 131 18.1 834 242 13.2 96.218.9 284 243 10.6 69.3 9.4 303 244 19.9 91.1 20.9 353 245 36.1 218.556.3 1675 246 38.5 299.6 85 3494 247 55.2 306 145.4 N/A 248 11.3 55.225.4 N/A 249 46.4 181.6 27.5 N/A 250 76.5 508.2 98.8 N/A 251 8.4 31.716.7 N/A 252 8 16.8 5.4 N/A 253 25.3 61.3 38.8 N/A 254 120.1 298.9 N/AN/A 255 30.7 69.1 12.4 N/A 256 24.5 86.8 51.2 N/A 257 20.3 88.7 30.6 N/A258 12.3 19.2 1.2 N/A 259 16.8 39.1 10.8 N/A 260 131.7 534.8 N/A N/A 26124.6 154.7 86.9 N/A 262 49.4 337.2 88.8 N/A 263 90.8 888.2 318.9 N/A 26430.4 118.7 26.8 N/A 265 7.6 19.3 10.8 N/A 266 29.4 182.5 32.5 N/A 26718.1 67.1 15.9 N/A 268 23.3 128.6 23.1 N/A 269 18.8 70.2 4.9 N/A 27016.9 44.8 10.5 N/A 271 44.9 137.3 8.6 N/A 272 17.9 55.2 14.7 N/A 27321.3 41.6 7.9 N/A 274 16.5 64.2 20.2 N/A 275 39.9 460.1 124.3 N/A 276640.7 4408.8 N/A N/A 277 29.8 242.6 74.9 779 278 22.7 186.3 108.5 858279 33.4 147.7 20.2 N/A 280 226.2 620.7 N/A N/A 281 23 140.8 65.3 N/A282 36.1 144.6 31.6 2304 283 17.1 83.7 18.1 1077 284 76.6 693.1 141.65741 285 103.4 961.7 N/A 10000 286 29.8 93.8 14.1 864 287 17.3 77.8 9.1N/A 288 16.1 80 7.7 N/A 289 18 119.4 52.4 N/A 290 17.3 158.3 80.5 N/A291 95.4 895.5 956.6 N/A 292 14.7 122.6 36.4 N/A 293 106.2 904.7 N/A N/A294 15.1 244.4 111.3 N/A 295 29 81.4 19.7 N/A 296 50.8 247.6 110.8 N/A297 121 737.2 N/A N/A 298 94.9 606.4 251.1 N/A 299 6.8 14.9 5.6 N/A 30014.8 57.4 13.3 N/A 301 6.1 32.6 4.7 52 302 11.8 26.7 13.7 74 303 14.128.7 4.6 73 304 22.1 68.3 10.3 136 305 10.7 47.2 5.8 75 306 23.3 95.24.3 239 307 25.5 39.8 395.1 N/A 308 11.3 28.8 14.5 329 309 7.6 18.1 18N/A 310 14.7 30.8 3.2 67 311 8.3 15.4 3.7 28 312 7.7 35.3 10 43 313 52.1230.2 107.6 N/A 314 14.2 30.7 13.9 66 315 16.5 50.2 12 164 316 18.8 47.59.4 165 317 25.9 69.7 6.6 104 318 6.6 15.8 3.5 32 319 17.8 85.6 9.3 160320 20.6 59.3 3.7 N/A 321 9.8 37.3 14.3 65 322 13.7 27.4 8.9 73 323 16.130.5 3.6 69 324 8.7 22 1.4 30 325 17.1 70.9 23.4 255 326 103.9 661.8203.1 N/A 327 13.2 22.8 11.7 N/A 328 14.9 109.7 19.4 N/A 329 112 751225.8 N/A 330 165.9 745.5 N/A N/A 331 18.9 137.3 34.5 N/A 332 11 48.329.8 N/A 333 963.6 6081 N/A N/A 334 6.6 28.5 18.1 79 335 68.7 221.2172.9 163 336 16.6 88.9 30.8 241 337 391.6 1085.9 N/A 1000 338 11 33.715 52 339 726.9 2657.9 N/A 5804 340 12.9 33.5 2.2 92 341 7.6 12 4.4 21342 12.4 32 7.6 58 343 15.1 50.4 20 80 344 27.1 233.5 58.7 168 345 7173887.4 N/A 3617 346 135 1472.2 N/A N/A 347 189.6 1812.1 N/A N/A 348 31.1135.4 71.8 N/A 349 101.1 627.6 131 N/A 350 21.7 185.6 43.4 N/A 351 133.51286.4 N/A N/A 352 89.6 1553.9 229.9 N/A 353 87.6 647.4 148.9 N/A 354 53542.9 137.6 N/A 355 210 2822.4 N/A N/A 356 159.5 2217.3 N/A N/A 357194.6 1446.7 N/A N/A 358 7.6 41.3 7.6 38 359 10.9 56.9 7 123 360 88.9833.3 277.9 N/A 361 11.7 74.4 9.2 90 362 4.4 16.9 4.7 19 363 5.5 22.73.3 35 364 104.8 972.1 N/A N/A 365 347.5 3719.7 N/A N/A 366 451.4 2866.2N/A N/A 367 37.1 89.4 41 N/A 368 22.6 69.6 5.5 159 369 34.3 55.4 5.2 92370 19.6 111.5 24.6 N/A 371 4.2 19.7 23.6 24 372 18.3 55 18.6 109 37329.7 233.8 116.5 N/A 374 9.8 58.5 23.9 43 375 155.4 749.7 N/A 1073 37693 428.3 168.4 1069 377 57.7 314.8 39.4 754 378 N/A N/A N/A N/A 379 8.821.8 4.8 54 380 7.1 14.7 6.3 41 381 10.3 24.7 15.1 N/A 382 20.5 62.9 8.8N/A 383 21.5 43.4 18.3 62 384 5.7 14 2.6 22 385 5.8 26.4 4.7 37 386 9.7101.9 9.8 67 387 52.7 497 429.3 327 388 22 71 18.6 75 389 13.4 26 1.3124 390 11.1 37.2 4.3 63 391 6.7 10.6 2 21 392 48.9 212.5 54.2 458 3936.4 52.8 9.3 58 394 7.5 31 3.5 39 395 26.4 102.8 146.9 146 396 26.5 87.5115.8 114 397 17.5 40.2 16.8 86 398 230.7 2422.2 N/A 8419 399 26.1 56.94.1 319 400 13.7 36.6 8.2 189 401 19 33.6 2.9 109 402 11.7 18.5 3.2 71403 22.3 37.1 2.1 182 404 12.2 31.2 20.7 94 405 8 28.2 12.7 N/A 406 12.254.9 19.1 73 407 14 47.5 19.7 42 408 30.2 239.8 72.6 N/A 409 8.9 12.73.3 N/A 410 8.7 14.3 3.9 N/A 411 150.2 1078.2 N/A N/A 412 17.3 89.7 13.6N/A 413 637 3424.7 N/A 5467 414 15.8 50.1 16.5 145 415 6.9 24 5.6 N/A416 8.6 38.6 8.6 N/A 417 32 58 204.9 89 418 340.2 473.3 N/A N/A 419106.5 176.3 N/A N/A 420 147.4 227.9 N/A N/A 421 25.7 61.9 70.1 159 42216.5 30.7 28.9 116 423 23.6 54.1 38.2 144 424 42.2 32.4 137.4 273 42531.2 70.3 74 195 426 238.4 457 N/A N/A 427 41.8 72.8 152.3 1122 428 47.5104.2 141.5 N/A 429 56.2 222.5 745.3 4107 430 334.7 542 N/A N/A 431 38.2102 47.8 854 432 32.2 81.2 9.5 239 433 20.2 48.5 2.7 90 434 6.2 45.2 7.732 435 12.4 35.2 2.7 57 436 19.3 96.2 8.7 182 437 21.8 87.2 9.4 95 43814.9 92.8 28.2 68 439 22 142.6 16.3 118 440 13.2 30 5 N/A 441 12.4 49.913.8 231 442 15 56.2 6.9 70 443 12.6 47.7 6.5 111 444 15.2 60.4 12.7 N/A445 19.6 161.3 17.2 89 446 26.2 94.8 52.8 241 447 24.8 163 98.3 N/A 44822.9 161.9 80.1 N/A 449 85.4 1111.1 417.2 N/A 450 20.8 180.6 38 137 45115.5 84.5 18.3 86 452 9.8 71.2 22.3 109 453 21.4 158.4 24.8 245 454 20.7189.5 64.3 195 455 25.8 83.8 16.6 231 456 17.7 42.9 11.9 75 457 74.8 395238.5 470 458 35.6 239.4 82.4 414 459 12.7 70 461.8 297 460 12.3 87.422.9 401 461 45.9 357.6 65.6 725 462 22.9 93 63.2 283 463 34.6 190.736.4 454 464 39.5 211.9 32.7 312 465 28.6 121.4 21.7 383 466 41.7 203.755.7 N/A 467 383.8 2091.3 N/A N/A 468 20.1 83.1 17.6 N/A 469 42.9 208.2139.2 N/A 470 12.5 95.1 29.6 N/A 471 44.7 391.4 88.2 N/A 472 22 171 47.3N/A 473 19.8 68.1 11 195 474 12.8 141.4 43.5 N/A 475 10.1 69.9 25.6 N/A476 9.3 62.8 19.5 N/A 477 19.4 173.3 34.7 N/A 478 59.9 613.7 116.5 N/A479 728.3 2778.9 N/A N/A 480 317.3 1708 N/A 1739 481 16.6 88.9 30.8 N/A482 47 N/A N/A 10000 483 127 508 N/A N/A 484 590.6 3508.1 N/A N/A 4853.7 30.7 32.3 N/A 486 397.9 2303.6 N/A N/A 487 5.5 35.1 88 78 488 8.4 7323.9 N/A 489 20.5 484.2 73.9 104 490 913.7 10000 N/A 10000 491 65.1 358N/A 269 492 20.1 80.5 30.6 55 493 12.8 166.2 17.2 79 494 55.2 307.3 N/A276 495 40.4 358.1 57.6 176 496 118.7 588.3 N/A 422 497 110.1 573.8 N/A896 498 71.9 216.1 171.4 194 499 322.1 446.8 N/A 3336 500 108.6 2197.9N/A 1205 501 276 3898.7 N/A 5553 502 78.1 1145.1 142.1 1034 503 103.7718.4 N/A 970 504 10.2 64.8 9.5 47 505 250.4 3282.6 N/A 1670 506 432.16553.4 N/A 2012 507 49.4 528.9 1223 399 508 45.1 211.1 110.1 292 50912.8 195.8 38.7 82 510 523.6 6442.1 N/A 10000 511 598 10000 N/A 1111 51265.7 719.4 235.1 1093 513 13.9 185.6 29 106 514 26.1 101.1 35.7 207 515141.8 1027.2 N/A 2392 516 114.8 720.7 N/A 944 517 265.9 10000 N/A 10000518 478 1164.2 N/A 4570 519 10.2 35.1 7.8 42 520 8.2 31.1 5.6 22 52159.6 402.5 N/A 723 522 12.2 98.4 9.6 56 523 11.2 39.3 7.4 63 524 25154.3 28 111 525 20.4 207.4 35.2 133 526 24.6 123.5 22.7 94 527 24.4443.8 104.2 261 528 6.4 14.7 3 18 529 115.8 1111.9 N/A 698 530 534.810000 N/A 10000 531 26.9 159.1 34.4 158 532 98.9 471.6 454.3 841 533454.3 6705.6 N/A 6786 534 107.5 2683.6 N/A 3297 535 173 1520.5 N/A 1050536 403.9 1511.9 N/A 2854 537 317.9 1394.1 N/A 3052 538 620.6 4423.4 N/A5231 539 434.8 2716.5 N/A 5008 540 329.1 2134.6 N/A 4435 541 10.6 89.4 5106 542 28.8 179.5 33.5 209 543 7.8 91.9 10 80 544 21.7 343 25.2 278 54590.6 N/A N/A 836 546 29.8 243.3 157.7 274 547 68.6 762.1 388 1382 54833.5 441.1 320.4 395 549 50.7 688.6 481 1088 550 45.2 724.2 218.7 1219551 60.5 1990.8 130.9 666 552 44.6 311.3 75.3 394 553 138.2 732.8 N/A1775 554 255.7 6537.2 N/A 1442 555 19.9 189.4 35 258 556 12.5 22.8 41.8114 557 29.1 266.5 45.2 420 558 27.7 192.5 34.2 345 559 55.3 508.7 100.1693 560 23.9 166.7 35.6 280 561 361.7 2985.3 N/A 7429 562 37.6 195.925.2 176 563 41.7 176.5 51.6 211 564 11.1 17.9 3.1 39 565 13.7 116.323.3 168 566 10.1 147.2 51.7 124 567 7.8 140.2 37.9 66 568 35.5 216.6141.4 331 569 20.8 59.9 9.9 40 570 7.2 28.9 6.5 44 571 8.9 55.3 5.3 48572 11.2 67.6 36.7 116 573 15.2 94.1 48.3 155 574 28.5 212.1 65.8 119575 33.2 165.7 219.1 144 576 439.5 3690.9 N/A 1217 577 203.6 1673.1 N/A602 578 9.8 43.7 7.6 51 579 9.8 27.4 4.1 32 580 8 25.3 7.4 55 581 8.421.4 3.3 35 582 18.2 32.9 11.4 62 583 46.3 308.9 109 642 584 13.7 110.723.3 226 585 32.3 304.7 33.4 289 586 25.7 158.9 10.9 251 587 30.8 96.913.2 95 588 58.8 513.1 91.4 467 589 57.4 716 136.5 677 590 92.3 443.3122.6 431 591 122.8 2320.8 N/A 2022 592 25 270.7 54.2 280 593 31.9 245.742.2 309 594 30.5 85.6 8.45 71 595 45.5 348.4 55.6 N/A 597 6 13.6 2.2 25598 10.9 59.1 10.2 48 599 17 35.8 4.8 94 600 14 79.4 17.7 113 601 1767.7 11 97 602 7.6 49 7.2 61 603 17.2 68 10 158 604 18.2 43.4 5.9 129605 784.1 3987.4 N/A 6980 606 15.1 119.6 51.7 226 607 21.1 69.4 23.3 320608 22.9 130.6 488.2 193 609 190.9 983.7 N/A 1113 610 27.1 195.1 142.4296 611 36 150.3 34.9 457 612 13.9 139.4 225.6 258 613 10 27.2 3.2 48614 19.3 49.8 9.5 76 615 9.6 24 8.9 62 616 23.6 67.9 10.9 N/A 617 44.9118.6 15 N/A 618 15.1 148.5 39.4 319 619 14.3 77.4 13.1 286 620 15.8 N/A19 333 621 16.4 83 22.6 260 622 23 196.5 104.8 582 623 31.3 139.5 20.7363 624 30.3 280.2 34.8 414 625 105.1 718.3 N/A 3513 626 20.4 112.71071.8 415 627 41 254.4 1667 917 628 18.3 272.7 79 259 629 13.7 125.943.4 293 630 16.8 87.5 80.6 270 631 29 244.9 23.6 312 632 38.9 98.9107.8 507 633 14.5 124.1 45.1 165 634 30.1 251.1 71.4 272 635 17.5 94.8222.9 228 636 30.7 158.7 100.8 315 637 263.6 1952 N/A 2112 638 21.4237.6 22.4 213 639 105.1 442.8 N/A 1131 640 47.3 166.4 801.5 508 64113.3 88.7 6.9 86 642 27.1 255.4 19.6 930 643 32.4 183.4 17.6 223 64425.1 203.8 19.7 185 645 12.4 86 10.6 89 646 30.9 207.8 23.5 159 647 34.9361.6 50.5 279 648 72 575.9 125.7 888 649 112 793.4 N/A 1029 650 149.61088.8 N/A 1017 651 6.5 53.9 48.9 78 652 14.9 181.6 177.5 190 653 12.339.5 228.7 108 654 10.2 90.6 10.5 114 655 27.5 79.7 19.8 149 656 6.3 354.3 54 657 15.5 86.5 17.7 91 658 19.4 159.3 161.1 191 659 14.7 133.314.6 267 660 16.2 106.9 9.1 168 661 36.2 142.4 48.9 274 662 9.8 42.410.4 46 663 492.1 5103.1 N/A 10000 664 3959.5 10000 N/A 10000 665 729.53613.2 N/A 10000 666 29.6 41.9 27.2 72 667 174.9 493.3 N/A 994 668 45.6133.5 66.1 604 669 22 59.1 28.8 402 670 18.4 67 17.5 194 671 20.7 75.123.1 159 672 13 52.3 23.9 148 673 11.1 65.5 21.4 157 674 39.3 105.4 3.2279 675 30.2 91 2.4 249 676 12.9 30.1 8 141 677 13.5 26.8 5 61 678 17.938.4 2.3 55 679 18 33.3 2.3 135 680 5.2 28.9 12 88 681 42.9 226.1 25.2311 682 24.9 53.3 4.9 106 683 16.5 90.2 11.5 196 684 15.2 40.9 4.3 122685 19.6 53.2 7.7 498 686 11 40.7 8.6 174 687 14.8 45.4 13.2 81 688 511.5 5.4 109 689 12.7 50.4 9 165 690 3.7 12.6 3.7 42 691 21.9 31.5 3 85692 9.3 38.9 7.8 128 693 6 63.3 14.1 183 694 27.7 74.2 4.8 161 695 21.882.1 28.6 204 696 42.4 61 11.7 277 697 34.7 93 8.4 382 698 6.1 16 81.5114 699 16 26.5 8.8 153 700 78.7 88.5 N/A 357 701 6.1 21.3 25.1 162 70210.7 48.3 10.5 130 703 7.2 26.3 14.7 63 704 21.9 87.4 10.9 218 705 4.617.8 24.3 131 706 17 121.7 16.5 4540 707 9.1 36.3 11.6 59 708 43 450 3721044 709 11 32 8 83 710 53 517 103 467 711 6 11 3 26 712 20 191 29 315713 17 276 90 284 714 32 303 103 747 715 34 132 66 158 716 125 765 N/A1151 717 23 473 268 1405 718 34 310 85 607 719 16 112 47 123 720 4353438 938 10000 721 14 30 30 58 722 2 10 3 15 723 3 10 2 13 724 15 95 1140 725 4 15 2 16 726 44 176 105 214 727 24 195 67 194 728 19 316 80 804729 7 21 13 35 730 5 12 5 16 731 5 15 8 27 732 96 455 N/A 472 733 4348002 N/A 10000 734 52 321 80 694 735 56 568 N/A 6169 736 53 993 N/A10000 737 69 295 105 10000 738 40 304 18 10000 739 68 301 96 10000 74043 320 119 8460 741 217 1315 N/A 5702 742 4 24 5 648 743 12 63 6 1119744 40 218 36 1109 745 128 966 N/A 10000 746 28 97 15 1283 747 19 66 121490 748 14 81 12 1999 749 25 152 15 2584 750 42 212 23 4308 751 48 25639 1530 752 143 2665 N/A 10000 753 13 72 7 943 754 7 73 16 543 755 1431197 483 1305 756 6 50 22 81 757 19 537 41 2375 758 29 164 15 570 759 11137 11 338 760 53 508 76 2594 761 18 134 13 394 762 12 116 11 239 763 22124 16 3272 764 79 247 418 351 765 578 3799 N/A 10000 766 23 361 54 351767 23 196 13 592 768 11 118 16 1984 769 12 162 36 6870 770 4 24 12 63771 9 26 4 52 772 8 24 4 30 773 12 10000 9 10000 774 8 45 6 51 775 3 165 26 776 10 46 11 94 777 3 13 3 25 778 23 129 19 192 779 19 66 13 58 78021 91 15 328 781 41 90 7 154 782 33 221 92 520 783 3 43 62 76 784 24 7717 796 785 37 142 20 1475 786 48 179 13 965 787 22 60 8 541 788 23 93 9983 789 23 159 8 1022 790 8 35 34 268 791 16 77 19 107 792 13 106 18 92793 8 47 11 76 794 5 32 7 29 795 16 245 25 122 796 5 34 7 21 797 10 3011 423 798 9 9 11 222 799 21 37 28 274 800 9 21 6 86 801 114 1078 N/A1744 802 176 818 N/A 1214 803 62 213 N/A 384 804 71 266 N/A 368 805 33319 72 301 806 33 180 59 276 807 5 21 6 55 808 6 27 5 51 809 8 37 9 73810 19 78 13 128 811 7 24 9 94 812 16 83 26 158 813 6 23 8 38 814 8 24 964 815 9 37 13 87 816 13 39 24 83 817 7 27 29 80 818 38 253 60 431 81923 149 55 245 N/A = not available

Synthetic Examples Synthesis of Synthetic Intermediates

Intermediate P1

4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile Part A:Preparation of O-(mesitylsulfonyl)hydroxylamine Step 1: Preparation oftert-butyl (mesitylsulfonyl)oxycarbamate

To a 0° C. solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (10.0g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) inMTBE (100 mL) was added TEA (14.46 mL, 48.01 mmol) drop-wise whilestirring. The resulting suspension was stirred at 0° C. for anadditional 30 min and then warmed to ambient temperature. The reactionwas then diluted with water (100 mL), adjusted to pH 4 with 1 NHCl_((aq)). The organic layer was dried (Na₂SO₄), filtered andconcentrated to yield the title compound initially as a yellowish oil,which upon drying overnight under high vacuum became a white solid(12.89 g, 89% yield). ¹H NMR (CDCl₃) δ 7.66 (br s, 1H), 6.98 (s, 2H),2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s, 9H).

Step 2: Preparation of O-(mesitylsulfonyl)hydroxylamine

To TFA (117 mL, 1521 mmol) at 0° C. was slowly added tert-butyl(mesitylsulfonyl)oxycarbamate (39.0 g, 124 mmol) over 25 min. Thereaction mixture was stirred at 0° C. for 1.5 h and then quenched withthe sequential addition of crushed ice and water. The resulting thicksuspension was vigorously stirred at ambient temperature for 5 min.Without allowing the filter cake to run dry, the solids were collectedby careful vacuum filtration followed by subsequent rinsing with water(4 L) until the filtrate reached pH 6 (Caution: explosion risk existswith dry compound at ambient temperature). The wet filter cake was takenup in DCM (150 mL) and the resulting biphasic solution was separated.The DCM layer was dried over MgSO₄ for 30 min and then filtered andrinsed with DCM (420 mL) to provide the title compound as a 0.22 Msolution in DCM

Part B: Preparation of4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile Step 1:Preparation of 1-amino-3-bromo-5-methoxypyridin-1-ium2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (Part A, 26.6 g, 117mmol) in DCM (570 mL) cooled to 0° C. was added3-bromo-5-methoxypyridine (22.1 g, 117 mmol) in portions. The reactionmixture was stirred for 1 h at 0° C. then treated with additional3-bromo-5-methoxypyridine (250 mg, 1.39 mmol) and stirred for anadditional 2 h at 0° C. The reaction mixture was diluted with Et₂O (600mL), stirred at 0° C. for 10 min and then vacuum filtered, rinsed withEt₂O (3×250 mL). Upon reduction in volume by about ⅓, the filtrateyielded additional precipitate which was collected by filtration. Bothfilter cakes were dried in vacuo to provide the title compound (39.3 g,83% yield). ¹H NMR (CDCl₃) δ 9.25 (br s, 1H), 8.99 (m, 1H), 8.74 (m,1H), 7.46 (m, 1H), 6.83 (s, 2H), 3.92 (s, 3H), 2.65 (s, 6H), 2.22 (s,3H).

Step 2: Preparation of Ethyl6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and Ethyl4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate

To a magnetically stirred white suspension of1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate(33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was addedTEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethylpropiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, thereaction was slowly quenched via portion-wise addition to rapidlystirring ice water (820 mL). The mixture was stirred at ambienttemperature for 10 min and then vacuum filtered. Solids collected wererinsed with water and air-dried, yielding the title compounds as anorange solid in an isomeric ratio of about 4:1 (by ¹H NMR) with the 6-Brisomer as the major isomer (21 g). The wet solid isomeric mixture (about75% w/w) was directly used in Step 3 without further purification. MS(apci) m/z=298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeOchemical shift in ¹H NMR (CDCl₃) δ 3.98 (6-Br isomer) vs. 3.83 (4-Brisomer).

Step 3: Preparation of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (P1) and4-bromo-6-methoxypyrazolo[1,5-a]pyridine

The isomeric mixture of ethyl6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl4-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate from Step 2 (15g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heatedat 80° C. for 90 min followed by stirring at ambient temperatureovernight. The resulting suspension was vacuum filtered and rinsed withwater. The aqueous filtrate and the filter cake were treatedindependently. The filter cake was taken up in MTBE and vacuum filteredto remove insoluble impurities. The MTBE filtrate was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to yield6-bromo-4-methoxypyrazolo[1,5-a]pyridine as a beige solid (about 98:26-/4- Br; 5.08 g). MS (apci) m/z=226.9, 228.9 (M+H). ¹H NMR (CDCl₃) δ8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H).Independently the original aqueous reaction mixture filtrate wasextracted with EtOAc. The combined organic extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. The crude residue was taken up inDCM (50 mL) and then filtered to remove insoluble solids. Concentrationof the DCM filtrate under vacuum followed by silica chromatography (0 to50% EtOAc/hexanes) yielded a second batch of6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate P1) as whitesolid (upper R_(f) spot, 2.06 g), as well as the minor isomer titlecompound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P2) alsoas white solid (lower R_(f) spot, 1.32 g). MS (apci) m/z=226.9, 228.9(M+H). ¹H NMR (CDCl₃) δ 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55(m, 1H), 3.80 (s, 3H).

Step 4: Preparation of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde

A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5.0 g, 22 mmol)in DMF (220 mL) was cooled to 0° C. and then slowly treated with POCl₃(6.2 mL, 66 mmol). The reaction was warmed to ambient temperature andstirred overnight. The reaction mixture was cooled to 0° C., quenchedwith water (220 mL), and basified with 6 M NaOH_((aq)) to pH 9-10. Thereaction mixture was stirred for 1 h and then vacuum filtered. Thesolids were rinsed sequentially with water and MTBE. The collected solidwas suspended in DCM (500 mL) and stirred in a sonicating bath for 30min and then vacuum filtered. The filtrate was retained, while thefilter cake was taken up in water (300 mL) and extracted with DCM. Theorganic extracts, along with the retained DCM filtrate, were combinedand dried over anhydrous Na₂SO₄, then filtered and concentrated in vacuoto provide the title compound (4.84 g, 86% yield). MS (apci), m/z=256.9(M+H).

Step 5: Preparation of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde Oxime

To a suspension of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (4.84 g, 19.0mmol) in EtOH (253 mL) at ambient temperature was added water (127 mL)and hydroxylamine hydrochloride (1.98 g, 28.5 mmol). After stirring at50° C. overnight, the reaction mixture was cooled to ambient temperatureand concentrated in vacuo. The residue was suspended in water (150 mL)and then quenched slowly with saturated NaHCO_(3(aq)) (30 mL). Afterstirring for 1 hour at ambient temperature the suspension was vacuumfiltered and the filter cake rinsed sequentially with H₂O (500 mL) andMTBE (100 mL) to yield the title compound as a 2:1 E/Z mixture (5.13 g,quantitative yield), which was used in the next step without furtherpurification. MS (apci) m/z=271.9 (M+H).

Step 6: Preparation of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

The E/Z mixture of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (4.95 g,18.33 mmol) in acetic anhydride (172.9 mL, 1833 mmol) was stirred at140° C. for 25 h, and then cooled to ambient temperature. The resultingsuspension was further cooled in an ice bath for 15 min and then vacuumfiltered and rinsed sequentially with water and MTBE to provide thetitle compound (3.74 g, 81% yield). ¹H NMR (d⁶-DMSO) δ 8.70 (s, 1H),8.60 (s, 1H), 7.78 (s, 1H), 3.83 (s, 3H).

Step 7: Preparation of4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

A slurry of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(50.0 g, 198.4 mmol) in DCE (500 mL) was treated with AlCl₃ (79.34 g,595.1 mmol). Under a N_(2(g)) atmosphere, the resulting mixture wasstirred 19 h at 76° C., before cooling to room temperature. Using THF(1750 mL) as a rinse solvent, the reaction mixture was poured into amechanically stirred suspension of sodium sulfate decahydrate (10 eq,639 g) in THF (1000 mL). After stirring overnight at ambienttemperature, the resulting suspension was filtered, and the solids wererinsed with additional THF (2×250 mL). The filtrate was concentrated invacuo, and the resulting solid was dried under high vacuum for 3 days toafford the title compound (46.18 g, 98% yield) in sufficient purity forsubsequent use. ¹H NMR (d⁶-DMSO) δ 10.48 (s, 1H), 8.58 (s, 1H), 8.38 (d,1H), 7.64 (3, 1H).

Intermediate P5

4-Bromo-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1; 4.0 g, 16.80 mmol) in DMA (100 mL) was treated withK₂CO_(3(s)) (7.0 g, 51 mmol) and iodoethane (2.0 mL, 25 mmol) and thenstirred for 3 hrs at 60° C. The reaction mixture was cooled to ambienttemperature and then quenched with 1:1 NH₄OH/Water. The resultingsuspension was filtered, and the solids were isolated to provide thetitle compound (4.35 g, 97% yield) in sufficient purity for subsequentuse.

Intermediate P6

6-Ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure vessel, a solution of4-bromo-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P5;500 mg, 1.88 mmol) in dioxane (9.40 mL) was treated sequentially with2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (629mg, 2.82 mmol), Pd(PPh₃)₄ (217 mg, 0.188 mmol) and 2 M Na₂CO_(3(aq))(4.70 mL, 9.40). The resulting mixture was sparged with Ar_((g)) andthen the vessel was sealed. The mixture was stirred 8 h at 90° C., andthen overnight at ambient temperature. The reaction mixture was dilutedwith water and extracted with EtOAc. The combined organic extracts werewashed with water and brine, dried over anhydrous Na₂SO_(4(s)), filteredand concentrated in vacuo. The crude residue was purified by silicachromatography (25-100% EtOAc in hexanes as the gradient eluent) tocleanly provide the title compound (500 mg, 94% yield). MS (apci)m/z=283.1 (M+H).

Intermediate P25

4-Bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of (2-bromoethoxy)(tert-butyl)dimethylsilane (451 μL, 2.10mmol), 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1; 500 mg, 2.10 mmol) and K₂CO_(3(s)) (871 mg, 6.30 mmol)in DMF (10.5 mL) was stirred for 1 day at 50° C. After cooling toambient temperature, the reaction mixture was diluted with EtOAc andwashed with water and brine. The resulting organic extracts weredirectly purified by silica chromatography (0-100% EtOAc/hexanes as thegradient eluent) to cleanly provide the title compound (420 mg, 49%yield).

Intermediate P26

6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure vessel, a solution of4-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P25; 420 mg, 1.06 mmol) in dioxane (10.6 mL) was treatedsequentially with2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (355mg, 1.59 mmol), Pd(PPh₃)₄ (61.2 mg, 0.530 mmol) and 2 M Na₂CO_(3(aq))(2.65 mL, 5.30). The resulting mixture was sparged with Ar_((g)) and thevessel was sealed. The mixture was stirred 8 h at 90° C., and thenovernight at ambient temperature. The reaction mixture was diluted withwater and extracted with EtOAc. The combined organic extracts werewashed with water (10 mL) and brine (10 mL), then were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The cruderesidue was purified by silica chromatography (using 0-15% MeOH in DCMas the gradient eluent) to afford impure title compound. The impurematerial was re-subjected to silica chromatography (0-50% EtOAc inHexanes as the gradient eluent) to cleanly provide the title compound(351 mg, 80% yield). ¹H NMR (400 MHz, DMSO-d₆-) δ: 8.81 (d, 1H, J=2.0Hz), 8.61 (s, 1H), 8.48 (d, 1H, J=2.7 Hz), 8.25 (td, 1H, J=7.8, 2.7 Hz),7.47 (d, 1H, J=1.9 Hz), 7.38 (dd, 1H, J=7.8, 2.3 Hz), 4.21 (t, 2H, J=4.3Hz), 3.97 (t, 2H, J=4.7 Hz), 0.86 (s, 9H), 0.08 (s, 6H).

Intermediate P41

4-Bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure vessel, a mixture of4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP1; 10.0 g, 42.0 mmol) and K₂CO_(3(s)) (17.4 g, 126 mmol) in DMF (50 mL)was treated with 2,2-dimethyloxirane (36.9 mL, 420 mmol). After sealingthe vessel, the reaction mixture was stirred for 12 h at 60° C., thenfor 12 h at 85° C. The mixture was allowed to cool to ambienttemperature. The room temperature mixture was poured into water (400mL), then stirred for 1 hour at ambient temperature. The resultantsuspension was vacuum filtered and the filter cake was rinsed withwater. The solids were collected and dried in vacuo to cleanly providethe title compound (11 g, 84% yield).

Intermediate P42

4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P41; 10.0 g, 32.2 mmol),2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10.8g, 48.4 mmol) and Pd(PPh₃)₄ (1.12 g, 0.967 mmol) in dioxane (200 mL) wastreated with 2 M Na₂CO_(3(aq)) (64.5 mL, 129 mmol). The resultingmixture was sparged with Ar_((g)), then stirred for 12 h at 85° C. underan atmosphere of N_(2(g)). After cooling to ambient temperature, theresultant mixture was poured into cold water (1.5 L). The pH of themixture was adjusted to about pH 6 with the addition of 10% citric acid.After stirring for 1 hour at ambient temperature, the resultantsuspension was vacuum filtered. The solids were collected and dried invacuo to cleanly provide the title compound (10 g, 95% yield).

Intermediate P46

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 100 mg, 0.306 mmol) in DMA (2.04 mL) was treatedsequentially with tert-butyl (4-methylpiperidin-4-yl)carbamate (98.5 mg,0.460 mmol) and DIEA (107 μL, 0.613 mmol). The resulting mixture wassparged with Ar_((g)), then stirred overnight at 90° C. After cooling toambient temperature, the reaction mixture was diluted with water andwashed with DCM. The combined organic extracts were washed with waterand brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (22.4 mg, 50% yield)in sufficient purity for step 2. MS (apci) m/z=521.3 (M+H).

Step 2: Preparation of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(160 mg, 0.307 mmol) in DCM (1.54 mL) was treated with TFA (1 mL, 13.8mmol). After stirring for 30 min at ambient temperature, the mixture wastreated with additional TFA (1 mL) and stirred an additional 1 hour atambient temperature. The reaction mixture was concentrated in vacuo andthe residue was purified by silica chromatography (1-9% MeOH in DCM with0.1-0.9% NH₄OH as the gradient eluent) to cleanly provide the titlecompound (110 mg, 85% yield). MS (apci) m/z=421.2 (M+H).

Intermediate P47

3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylicAcid Step 1: Preparation of methyl3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate

A solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 103.4 mg, 0.3169 mmol) in DMA (2.11 mL) was treatedsequentially with methyl 3-azabicyclo[3.1.1]heptane-6-carboxylate (88.52mg, 0.5703 mmol) and DIEA (110.7 μL, 0.6337 mmol) and then sparged withAr_((g)) for 5 min. The mixture was stirred overnight at 90° C., thenfor 4 h at 100° C., before introducing TEA (0.2 mL). The mixture wasstirred overnight at 100° C., then for 4 days at 90° C. After cooling toambient temperature, the reaction mixture was diluted with water andwashed with DCM. The combined organic extracts were washed with waterand brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The crude residue was purified by silicachromatography (1-9% MeOH in DCM as the gradient eluent) to afford thetitle compound (134 mg, 58% yield). MS (apci) m/z=462.2 (M+H).

Step 2: Preparation of3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylicAcid

A solution of methyl3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate(134 mg, 0.290 mmol) in EtOH (2.90 mL) was treated with 2 M NaOH(aq)(436 μL). After stirring overnight at ambient temperature, the mixturewas brought to pH 4 with the addition of 2.0 N HCl_((aq)), and then theaqueous layer was returned to pH 7 with the addition of saturatedNaHCO_(3(aq)). The aqueous phase was extracted with DCM. The combinedorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (100 mg, 77% yield). MS (apci) m/z=448.2 (M+H).

Intermediate P48

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate.A solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 2.535 g, 7.768 mmol) in DMSO (6.1 mL) was treatedsequentially with tert-butyl (4-methylpiperidin-4-yl)carbamate (1.998mg, 9.322 mmol) and DIEA (4.06 mL, 23.3 mmol). The resulting mixturestirred overnight at 90° C. After cooling to ambient temperature, thereaction mixture was poured into 80 mL water and diluted with 80 mLheptane and stirred for 1 hour. The suspension was filtered and thesolids were rinsed with 25 mL water then 25 mL heptane. The isolatedsolids were dried under vacuum for 18 hours to afford the title compound(4.04 g, 99.9% yield) in sufficient purity for step 2. MS (apci)m/z=521.3 (M+H)

Step 2: Preparation of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. A solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(4.04 g, 7.76 mmol) in DCM (20 mL) was cooled to 0° C. The reaction wastreated with TFA (5.98 mL) and allowed to warm to RT. After stirring for30 min at ambient the reaction mixture was concentrated in vacuo. Theresidue was dissolved in MeOH (20 mL) and cooled to 0° C. and thentreated with Hydrochloric acid, 5 to 6N solution in 2-propanol (15.5 mL,77.5 mmol) and stirred for 15 min at 0° C. The reaction was diluted with20 mL MTBE, filtered, and solids were rinsed with 20 mL 1:1 MTBE: MeOH.The isolated solids were dried under vacuum to cleanly provide the titlecompound (3.37 g, 88% yield). MS (apci) m/z=421.2 (M+H).

Intermediate P49

(R)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

Step 1: Preparation of tert-butyl(R)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 750 mg, 2.30 mmol) and(R)-(3-Methyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester HCl (644mg, 3.22 mmol) in DMSO (4.6 mL) was added DIEA (1.2 mL, 6.89 mmol). Thereaction mixture was stirred 12 h at 90° C. After cooling to ambienttemperature, the reaction mixture was diluted into cold water andstirred for 2 h at ambient temperature. The suspension was filtered andthe solids were rinsed with water. The isolated solids were dried undervacuum for 48 h to afford the title compound (1.05 g, 90% yield) insufficient purity for step 2. MS (apci) m/z=507.3 (M+H)

Step 2:(R)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate). To a solution of(R)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate(1.05 g, 2.07 mmol) in 3 mL DCM was treated with TFA (3 mL, 39 mmol).The reaction mixture was stirred for 4 h at ambient temperature, andthen concentrated in vacuo. The residue was diluted with DCM (4 mL) andtoluene (1 mL) and stirred at ambient temperature for 15 min. Themixture was concentrated in vacuo and dried under vacuum for 2 days toafford the title compound with quantitative yield. MS (apci) m/z=407.3(M+H).

Intermediate P50

(S)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

Step 1: Preparation of tert-butyl(S)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 700 mg, 2.15 mmol) and(S)-(3-Methyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester HCl (601mg, 3.0 mmol) in DMSO (4.3 mL) was added DIEA (1.1 mL, 6.44 mmol). Thereaction mixture was stirred 12 h at 90° C. After cooling to ambienttemperature, the reaction mixture was diluted into cold water andstirred for 2 h at ambient temperature. The suspension was filtered andthe solids were rinsed with water. The isolated solids were dried undervacuum for 48 h to afford the title compound (950 mg, 87% yield) insufficient purity for step 2. MS (apci) m/z=507.3 (M+H)

Step 2: Preparation of(S)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate). To a solution of tert-butyl(S)-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate(950 mg, 1.88 mmol) in 3 mL DCM was treated with TFA (3 mL, 39 mmol).The reaction mixture was stirred for 4 h at ambient temperature, andthen concentrated in vacuo. The residue was diluted with DCM (4 mL) andtoluene (1 mL) and stirred at ambient temperature for 15 min. Themixture was concentrated in vacuo and dried under vacuum for 2 daysafford the title compound with quantitive yield. MS (apci) m/z=407.2(M+H).

Intermediate P51

4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

Step 1:Preparation of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 850 mg, 2.60 mmol) and3-(tert-butoxycarbonylamino)pyrrolidine (679 mg, 3.65 mmol) in DMSO (5.2mL) was added DIEA (1.36 mL, 7.81 mmol). The reaction mixture wasstirred 12 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted into cold water and stirred for 2 h atambient temperature. The suspension was filtered and the solids wererinsed with water. The isolated solids were dried under vacuum for 48 hto afford the title compound (1.26 g, 98% yield) in sufficient purityfor step 2. MS (apci) m/z=493.3 (M+H)

Step 2: Preparation of4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate). To a solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(950 mg, 1.88 mmol) in 3 mL DCM was treated with TFA (3 mL, 39 mmol).The reaction mixture was stirred for 4 h at ambient temperature, andthen concentrated in vacuo. The residue was diluted with DCM (4 mL) andtoluene (1 mL) and stirred at ambient temperature for 15 min. Themixture was concentrated in vacuo and dried under vacuum for 2 daysafford the title compound with quantitative yield. MS (apci) m/z=393.2(M+H).

Intermediate P52

6-ethoxy-4-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.500 g, 1.77 mmol) in DMSO (3.5 mL) was added TEA(0.741 mL, 5.31 mmol) and piperidin-4-ol (269 mg, 2.66 mmol). Thereaction mixture was stirred at 70° C. for 5 h. After cooling to ambienttemperature, the reaction mixture was poured into ice water. Theresultant solids were isolated by vacuum filtration to afford the titlecompound (501 mg, 1.38 mmol, 77.8% yield). MS (apci) m/z=364.2 (M+H).

Intermediate P53

4-(6-(4-benzyl-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 30 mg, 0.106 mmol) in DMA (0.5 mL) was added TEA(0.044 mL, 0.319 mmol) and 4-benzylpiperidin-4-ol (40.7 mg, 0.213 mmol)The reaction mixture was stirred at 90° C. for 24 h. After cooling toambient temperature, the reaction mixture was diluted with DCM andwashed with saturated NH₄Cl_((aq)) then water. The combined aqueouswashes were further extracted with DCM, and the combined organicextracts were dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by silica chromatography (30-100% EtOAcin hexanes as the gradient eluent) to afford the title compound (39 mg,0.0860 mmol, 80.9% yield). MS (apci) m/z=454.2 (M+H).

Intermediate P54

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-ylthio)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 210 mg, 0.64 mmol) and2-(piperidin-4-ylsulfanyl)pyridine (357 mg, 1.84 mmol) in DMA (1.6 mL)was added TEA (628 μL, 4.50 mmol). The reaction mixture was stirredovernight at 95° C. After cooling to ambient temperature, the reactionmixture was diluted water and extracted with EtOAc. The organic extractswere washed with water and brine. The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The residuewas purified by silica chromatography (10-90% EtOAc in Hexanes to affordthe title compound (20 mg, 61% yield). MS (apci) m/z=501.2 (M+H).

Intermediate P55

4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 100.5 mg, 0.3560 mmol) in DMSO (3 ml) was added(4-benzylpiperidin-4-yl)methanol hydrochloride (151.5 mg, 0.6267 mmol)and cesium carbonate (812.0 mg, 2.492 mmol). The reaction mixture wasstirred at 60° C. for 24 h. After cooling to ambient temperature, thereaction mixture was diluted with DCM and washed with water andsaturated NH₄Cl_((aq)). The combined aqueous layers were extracted withDCM, and the combined organic extracts were dried over anhydrousNa₂SO_(4(s)) and concentrated. The residue was purified by silicachromatography (0-100% EtOAc in hexanes as the gradient eluent) toafford the title compound (118.2 mg, 0.2528 mmol, 71.00% yield). MS(apci) m/z=468.2 (M+H).

Intermediate P56

4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of methyl4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate.To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 303.4 mg, 1.075 mmol) in DMSO (21.50 mL) was added4-N-Boc-amino-piperidine-4-carboxylic acid methyl ester (416.5 mg, 1.612mmol) and potassium carbonate (297.1 mg, 2.150 mmol). The reactionmixture was stirred at 110° C. for 72 h. The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organicextracts were dried over anhydrous MgSO_(4(s)) and concentrated invacuo. The resultant crude residue was purified by silica chromatography(0-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (76.7 mg, 13.7% yield) in sufficient purity for step 2. MS(apci) m/z=521.2 (M+H).

Step 2: Preparation of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate.To a solution of lithium borohydride (0.0120 mL, 0.365 mmol) in THF(0.912 mL) was added methyl4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate(47.5 mg, 0.0912 mmol). The reaction mixture was stirred at rt for 2 h.The reaction mixture was concentrated in vacuo, and the residue wasdiluted with EtOAc and washed with brine. The organic extract was driedover anhydrous MgSO_(4(s)) and concentrated in vacuo to afford the titlecompound as crude product (65.9 mg), which was used in the next stepwithout further purifications. MS (apci) m/z=493.2 (M+H).

Step 3: Preparation of4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate(65.9 mg, 0.134 mmol) in DCM (1 mL) was treated with TFA (0.2 mL, 2.68mmol). The reaction mixture was stirred at rt 30 min then concentratedin vacuo. The residue was taken up in DCM and washed with saturatedNa₂CO₃. The aqueous fraction was extracted with DCM, and the combinedorganic extracts were dried over anhydrous MgSO_(4(s)) and concentratedin vacuo to afford the title compound (35.6 mg, 68% yield). MS (apci)m/z=393.2 (M+H).

Intermediate P57

tert-butyl(R)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.147 g, 0.521 mmol) in DMSO (1 mL) was addedtert-butyl (R)-piperidin-3-ylcarbamate (209 mg, 1.04 mmol) and potassiumcarbonate (216 mg, 1.56 mmol). The reaction mixture was heated to 110°C. for 72 h. After cooling to ambient temperature, the reaction mixturewas diluted with DCM and quenched with saturated NH₄Cl and extractedinto additional DCM. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (100 mg, 0.216 mmol, 41.5%yield). MS (apci) m/z=463.2 (M+H).

Intermediate P58

4-(6-((3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of (3S,4S)-tert-butyl3-azido-4-hydroxypyrrolidine-1-carboxylate

A solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate(15.42 g, 83.25 mmol),(R)-N,N′-Bis(3,5-Di-tert-butylsalicylidene)-1,2-cyclohexanediaminochromium(III)chloride (0.5904 g, 0.8325 mmol), potassium carbonate (13.81 g, 99.90mmol), and azidotrimethylsilane (12.79 ml, 91.58 mmol) was sparged withnitrogen and stirred at rt for 24 h. The reaction mixture was treatedwith silica gel (30 g) and water (2 mL) and stirred at rt for anadditional 72 h. The solution was filtered through a pad of Celite® andconcentrated in vacuo. The residue was purified by silica chromatography(20-50% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (18.5 g, 81.05 mmol, 97.36% yield) in sufficient purity forstep 2.

Step 2: Preparation of (3S,4S)-4-azidopyrrolidin-3-ol Dihydrochloride

A solution of tert-butyl(3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate (0.500 g, 2.19 mmol)in DCM (2.19 mL) was treated with 6M HCl in IPA (4.5 mL, 27 mmol). Thereaction mixture was stirred at rt for 4 h, at which time the reactionmixture was concentrated in vacuo to afford the title compound (assumedtheoretical yield, 0.440 g, 2.19 mmol) in sufficient purity for step 3.MS (apci) m/z=129.1 (M+H).

Step 3: Preparation of4-(6-((3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.300 g, 1.06 mmol) in DMSO (2 mL) was addedN-ethyl-N-isopropylpropan-2-amine (3.70 mL, 21.3 mmol) and(3S,4S)-4-azidopyrrolidin-3-ol dihydrochloride (0.427 g, 2.13 mmol) Thereaction mixture was stirred 100° C. for 24 h. After cooling to ambienttemperature, the reaction mixture was quenched with saturatedNH₄Cl_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (20-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.220 g, 0.564 mmol,53.0% yield over two steps). MS (apci) m/z=391.15 (M+H).

Intermediate P59

4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of (3R,4R)-tert-butyl3-azido-4-hydroxypyrrolidine-1-carboxylate

A solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate(15.42 g, 83.25 mmol),(1S,2S)-(−)-[1,2-Cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)]chromium(III) chloride (1.181 g, 1.665 mmol), and azidotrimethylsilane (12.79ml, 91.58 mmol) was sparged with nitrogen and stirred at rt for 24 h. Tothis was added potassium carbonate (13.81 g, 99.90 mmol) in MeOH (100mL), and the reaction mixture was stirred an additional 5 h at rt. Thesolution was filtered through a pad of Celite® and concentrated invacuo. The residue was taken up in EtOAc and water. The aqueous fractionwas extracted with EtOAc, and the combined organic extracts were washedsuccessively with saturated NaHCO_(3(aq)), water, and brine. They weredried over anhydrous MgSO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (20% EtOAc in hexanes as theeluent) to afford the title compound (18.5 g, 81.05 mmol, 97.36% yield)in sufficient purity for step 2.

Step 2: Preparation of (3R,4R)-4-azidopyrrolidin-3-ol Dihydrochloride

A solution of tert-butyl(3R,4R)-3-azido-4-hydroxypyrrolidine-1-carboxylate (0.500 g, 2.19 mmol)in DCM (2.19 mL) was treated with 6M HCl in IPA (4.5 mL, 27 mmol). Thereaction mixture was stirred at rt for 4 h, at which time the reactionmixture was concentrated in vacuo to afford the title compound (assumedtheoretical yield, 0.440 g, 2.19 mmol) in sufficient purity for step 3.MS (apci) m/z=129.1 (M+H).

Step 3: Preparation of4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.300 g, 1.06 mmol) in DMSO (2 mL) was addedN-ethyl-N-isopropylpropan-2-amine (3.70 mL, 21.3 mmol) and(3R,4R)-4-azidopyrrolidin-3-ol dihydrochloride (0.427 g, 2.13 mmol) Thereaction mixture was stirred 100° C. for 24 h. After cooling to ambienttemperature, the reaction mixture was quenched with saturatedNH₄Cl_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (20-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.205 g, 0.525 mmol,49.4% yield over two steps). MS (apci) m/z=391.2 (M+H).

Intermediate P60

tert-butyl((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.215 g, 0.762 mmol) in DMSO (1.5 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.663 ml, 3.81 mmol) and tert-butyl((3R,4S)-4-hydroxypyrrolidin-3-yl)carbamate (0.231 g, 1.14 mmol). Thereaction mixture was stirred 100° C. for 24 h. After cooling to ambienttemperature, the reaction mixture was quenched with saturatedNH₄Cl_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (20-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.347 g, 0.747 mmol,98.1% yield). MS (apci) m/z=465.3 (M+H).

Intermediate P61

tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.215 g, 0.762 mmol) in DMSO (1.5 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.663 ml, 3.81 mmol) and tert-butyl((3S,4R)-4-hydroxypyrrolidin-3-yl)carbamate (0.231 g, 1.14 mmol). Thereaction mixture was stirred 100° C. for 24 h. After cooling to ambienttemperature, the reaction mixture was quenched with saturatedNH₄Cl_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.284 g, 0.611 mmol,80.3% yield). MS (apci) m/z=465.2 (M+H).

Intermediate P62

tert-butyl((3R,5S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.060 g, 0.21 mmol) in DMSO (0.4 mL) was addedpotassium carbonate (0.15 g, 1.1 mmol) and tert-butyl((3R,5S)-5-(trifluoromethyl)piperidin-3-yl)carbamate (0.171 g, 0.638mmol). The reaction mixture was stirred at 110° C. for 24 h. Aftercooling to ambient temperature, the reaction mixture was quenched withsaturated NH₄Cl_((aq)) and extracted into DCM. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by silica chromatography (0-100% EtOAcin hexanes as the gradient eluent) to afford the title compound (0.0538g 47.7% yield) in sufficient purity for step 2. MS (apci) m/z=531.2(M+H).

Intermediate P63

4-(6-((1R,5S,6r)-6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

Step 1: Preparation of tert-butyl((1R,5S,6r)-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 200 mg, 0.57 mmol) and tert-butyl((1R,5S,6r)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate(169 mg, 0.80 mmol)in DMSO (0.57 mL) was added DIEA (298 μL, 1.71 mmol). Under a N_(2(g))atmosphere, reaction was stirred overnight at 90° C. After cooling toambient temperature, the reaction mixture was diluted with water (5.7mL). The suspension was filtered and the solids were rinsed with water(3×5 mL) then MTBE (3×5 mL). The isolated solids were dried under vacuumwhile the MTBE filtrate was concentrated in vacuo. The filtrate residuewas purified by C18 reverse phase chromatography (5-50% ACN in water).The precipitate solids and chromatography product were combined andconcentrated in vacuo to cleanly provide the title compound (292 mg, 98%yield) in sufficient purity for step 2. MS (apci) m/z=519.20 (M+H)

Step 2: Preparation of4-(6-((1R,5S,6r)-6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. To a solution of tert-butyl((1R,5S,6r)-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate(148 mg, 0.29 mmol) in MeOH (571 μL) was added HCl (conc.) (476 μL, 5.71mmol) dropwise. The reaction was stirred for 2 h at ambient temperature.The reaction was diluted with EtOAc (1 mL) and was stirred at ambienttemperature for 10 minutes. MTBE (1 mL) was added and a suspensionformed. The suspension was filtered and solids were rinsed with 10% MeOHin MTBE (3×1 mL) to cleanly provide the title compound (114 mg, 81%yield). MS (apci) m/z=419.15 (M+H).

Intermediate P64

4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 205 mg, 0.628 mmol) and tert-butylpiperidin-4-ylcarbamate (252 mg, 1.26 mmol) in DMA (2.09 mL) was addedDIEA (549 μL, 3.14 mmol). The reaction was stirred 2 h at 95° C. Aftercooling to ambient temperature, the reaction mixture was diluted withwater and extracted with EtOAc. The organic extracts were washed withwater and brine. The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (assumed quantitative yield, 319 mg) in sufficient purity forstep 2. MS (apci) m/z=507.20 (M+H)

Step 2: Preparation of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate(319 mg, 0.63 mmol) in DCM (3.15 mL) was added TFA (3.14 mL, 40.9 mmol).The reaction was stirred for 30 min at ambient temperature. The reactionwas concentrated in vacuo. The residue was resuspended in DCM andpurified using silica chromatography (1-9% MeOH in DCM with 0.1-0.9%NH₄OH as the gradient eluent) to cleanly provide the title compound (37mg, 53% yield) MS (apci) m/z=407.2 (M+H).

Intermediate P65

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicAcid

Step 1: Preparation of methyl1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 1.04 mg, 3.19 mmol) and4-Methyl-piperidine-4-carboxylic acid methyl ester (1.00 mg, 6.37 mmol)in DMSO (3.2 mL) was added DIEA (1.67 mL, 9.56 mmol). The reaction wasstirred 16 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted with EtOAc. Theorganic extracts were washed with water and brine. The organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated invacuo. The residue was purified using silica chromatography (30-100%Hexanes to EtOAc) to afford the title compound (1.40 g, 95% yield) insufficient purity for step 2. MS (apci) m/z=464.2 (M+H).

Step 2: Preparation of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid. To a solution of methyl1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate(1.40 g, 3.02 mmol) in THF (15 mL) and MeOH (15 mL) and treated withpotassium hydroxide (4.53 mL, 9.06 mmol). The reaction was stirred for48 h at ambient temperature. The reaction was concentrated in vacuo. Theresidue was diluted with water and extracted with Et₂O. The aqueouslayer was acidified to pH 5 using 4N HCl and extracted with 4:1 DCM:IPA.The combined organic extracts were washed with water. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (1.20 g, 88% yield)in sufficient purity for step 2. MS (apci) m/z=450.2

Intermediate P66

4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure vessel, a solution of4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP1; 15.4 g, 64.7 mmol) in dioxane (320 mL) was treated sequentially with2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15.2g, 67.9 mmol), Pd(PPh₃)₄ (3.74 g, 3.23 mmol) and 2 M Na₂CO_(3(aq)) (97mL, 194 mmol). The resulting mixture was sparged with Ar_((g)) and thenthe vessel was sealed. The mixture was stirred 16 h at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withMTBE and extracted with 1 M NaOH. The combined aqueous layers wereextracted with MTBE. The combined aqueous layers were acidified to pH 4with 4 M HCl. The suspension was filtered and washed with water tocleanly provide the title compound (14.8 g, 72% yield). MS (apci)m/z=253.1 (M−H)¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.48-8.47 (d,1H), 8.41-8.40 (d, 1H), 8.26-8.21 (m, 1H), 7.38-7.36 (m, 1H), 7.31-7.30(d, 1H).

Intermediate P67

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P66; 3.0 g, 9.44 mmol) and tert-butyl4-methylpiperidin-4-ylcarbamate (2.83 mg, 13.2 mmol) in DMSO (12 mL) wasadded DIEA (4.93 mL, 28.3 mmol). The reaction was stirred 16 h at 90° C.After cooling to ambient temperature, the reaction mixture was dilutedinto water and acidified to pH 5 using a 10% citric acid solution andstirred for 15 min at ambient temperature. The suspension was filteredand the precipitate was rinsed with water. The isolated solids weredissolved in 4:1 DCM:IPA and dried over anhydrous Na₂SO_(4(s)), filteredand concentrated in vacuo. The residue was purified using silicachromatography (5-75% EtOAc in DCM) to afford the title compound(assumed theoretical yield, 4.23 g) in sufficient purity for step 2. MS(apci) m/z=449.3 (M+H)

Step 2: Preparation of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride To a solution of tert-butyl(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(assumed 4.23 g, 9.44 mmol) in MeOH (30 mL) was added HCl (5-6 Nsolution in 2-propanol, 28.3 mL, 142 mmol). The reaction was stirred for2.5 h at ambient temperature. The reaction was diluted with MTBE (30 mL)and stirred for 30 min at ambient temperature. The suspension wasfiltered and washed with MTBE (50 mL) to cleanly provide the titlecompound (2.18 g, 55% yield over two steps) MS (apci) m/z=349.2 (M+H).

Intermediate P68

N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P67; 503 mg, 1.19 mmol),5-fluoro-2-methylbenzoic acid (552 mg, 3.58 mmol), and HATU (1.36 g,3.58 mmol) in DMSO (5 mL) was added DIEA (1.7 mL, 9.55 mmol). Thereaction was stirred 16 h at ambient temperature. The reaction mixturewas diluted with THF (4 mL) and treated with NaOH (5.97 mL, 11.9 mmol)and stirred for 4 h at ambient temperature. The reaction wasconcentrated in vacuo. The residue was diluted with EtOAc and washedwith water. The pH was adjusted to pH 5 with AcOH and then extractedwith EtOAc. The organic extracts were washed with brine. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified using silicachromatography (50-100% Hexanes to EtOAc) to afford the title compound(534 mg, 92% yield) in sufficient purity for step 2. MS (apci) m/z=485.2(M+H).

Intermediate P69

methyl4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.700 g, 2.480 mmol) in DMSO (4.96 mL) was added DIEA(1.296 mL, 7.439 mmol) and methyl4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (0.8968 g, 3.472mmol). The reaction mixture was stirred 90° C. for 24 h. After coolingto ambient temperature, the reaction mixture was quenched water andextracted into EtOAc. The combined organic extracts were washed withsaturated NaCl_((aq)), dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(10-90% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (1.003 g, 1.927 mmol, 77.69% yield). MS (apci) m/z=521.3 (M+H).

Intermediate P70

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-5-fluoro-2-methylbenzamideStep 1: Preparation of methyl4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

A solution of methyl4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate(Intermediate P69, 0.8 g, 1.5 mmol) in DCM was treated with TFA. Thereaction mixture was stirred at rt for 24 h, then concentrated in vacuo.HCl in iPrOH (6N) was added to the mixture to precipitate product. Thesuspension was stirred at RT for 1 h then concentrated, affording thetitle compound (assumed theoretical yield, 0.65 g, 1.5 mmol) insufficient purity for step 2. MS (apci) m/z=421.25 (M+H).

Step 2: Preparation of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(5-fluoro-2-methylbenzamido)piperidine-4-carboxylate.To a solution of methyl4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate(0.65 g, 1.5 mmol) in DCM (31 mL) was added 5-fluoro-2-methylbenzoicacid (0.36 g, 2.3 mmol) and HATU (0.88 g, 2.3 mmol). The reactionmixture was stirred at rt for 1 h, at which time a catalytic amount ofDMAP was added. The reaction mixture was stirred at 50° C. for 1 h, thencooled to RT and purified directly by silica chromatography (0-100%EtOAc in Hexanes then 1-10% MeOH in CHCl₃ as the gradient eluent) toafford the title compound (0.8 g, 1.4 mmol, 93% yield over two steps) insufficient purity for step 3. MS (apci) m/z=557.2 (M+H).

Step 3: Preparation ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide.To a solution of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(5-fluoro-2-methylbenzamido)piperidine-4-carboxylate(750 mg, 1.35 mmol) in THF (26.949 mL) at 0° C. was added lithiumborohydride (117 mg, 5.39 mmol). The reaction mixture was stirred at 0°C. for 1 h. The reaction mixture was diluted with EtOAc and washed witha 10% aqueous citric acid solution. The organic extract was dried andconcentrated in vacuo. The residue was purified by silica chromatography(0-100% EtOAc in Hexanes then 1-10% MeOH in EtOAc as the gradienteluent) to afford the title compound (700 mg, 1.32 mmol, 98.3% yield) insufficient purity for step 4. MS (apci) m/z=529.1 (M+H).

Step 4: Preparation ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-5-fluoro-2-methylbenzamide.To a solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide(100 mg, 0.189 mmol) in DCM (0.946 mL) at 0° C. was added3-oxo-115-benzo[d][1,2]iodaoxole-1,1,1 (3H)-triyl triacetate (201 mg,0.473 mmol). The reaction mixture was warmed to rt and stirred at thattemperature for 1 h, at which time additional3-oxo-115-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (201 mg,0.473 mmol) was added. The reaction mixture was stirred at rt anadditional 15 min, then quenched with EtOAc and saturated NaHCO_(3(aq)).The organic extract was washed with Na₂S₂O_(3(aq)), dried, andconcentrated in vacuo. The residue was purified by silica chromatography(0-100% EtOAc in Hexanes then 1-10% MeOH in EtOAc as the gradienteluent) to afford the title compound (358 mg, 55.3% yield). MS (apci)m/z=527.15 (M+H).

Intermediate P71

tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate.To a solution of methyl4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate(Intermediate P69, 1.00 g, 1.92 mmol) in THF (12.8 mL) at 0° C. wasadded lithium borohydride (0.167 g, 7.68 mmol). The reaction mixture wasallowed to reach rt and stirred at this temperature for 24 h. Thereaction mixture was quenched with water, and the residual solids wereremoved by filtration. The filtrate was extracted with EtOAc, and thecombined organic extracts were washed with saturated NaCl_((aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)) and concentratedin vacuo. The residue was purified by silica chromatography (10-90%EtOAc in hexanes as the gradient eluent) to afford the title compound(0.832 g, 1.69 mmol, 87.9% yield) in sufficient purity for step 2. MS(apci) m/z=493.3 (M+H).

Step 2: Preparation of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate

To a solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate(0.832 g, 1.69 mmol) in THF (16.9 mL) was added3-oxo-115-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (0.832 g,1.69 mmol). The reaction mixture was stirred at rt for 24 h thenquenched with water. The mixture was extracted with EtOAc, and thecombined organic extracts were washed with saturated NaCl_((aq)). Theorganic extracts were concentrated in vacuo, and the residue waspurified by silica chromatography (10-90% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.594 g, 1.21 mmol, 71.7%yield). MS (apci) m/z=491.2 (M+H).

Intermediate P72

4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate.To a mixture of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(0.594 g, 1.21 mmol) in DCM (0.077 mL) was added dimethylaminehydrochloride (0.197 g, 2.42 mmol) and DIEA (0.443 mL, 2.54 mmol). Thismixture was stirred at rt for 15 min, then sodium triacetoxyborohydride(0.385 g, 1.82 mmol) was slowly added. The reaction mixture was stirredat rt for 24 h then quenched with water. The solution was extracted withEtOAc, and the combined organic extracts were washed with saturatedNaCl_((aq)). The organic extracts were dried over anhydrous Na₂SO_(4(s))and concentrated in vacuo, and the residue was purified by silicachromatography (10-90% EtOAc in hexanes as the gradient eluent) toafford the title compound (0.181 g, 0.348 mmol, 28.8% yield) insufficient purity for step 2. MS (apci) m/z=520.3 (M+H).

Step 2: Preparation of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A mixture of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate(0.181 g, 0.348 mmol) in DCM (0.02 mL) was treated with TFA (0.0268 mL).The reaction mixture was stirred at rt. The reaction mixture wasconcentrated in vacuo, resuspended in DCM, and washed successively withsaturated NaHCO_(3(aq)) and saturated NaCl_((aq)). The organic extractwas dried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo toafford the title compound (0.145 g, 0.346 mmol, 99.2% yield). MS (apci)m/z=420.3 (M+H).

Intermediate P73

4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)carbamate.To a solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(Intermediate P71, 400 mg, 0.815 mmol) in DCM (4.077 mL) was addedmorpholine (0.07703 mL, 0.815 mmol) and sodium triacetoxyborohydride(346 mg, 1.63 mmol). The reaction mixture was stirred at rt for 72 h.The reaction mixture was concentrated in vacuo, and the residue waspurified by C-18 reverse phase chromatography (5-95% ACN in water [+0.1%TFA] as the gradient eluent). The fractions containing the desiredproduct were diluted with 4:1 DCM/IPA and washed successively withsaturated NaHCO_(3(aq)) and saturated NaCl_((aq)). The organic extractwas dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo to afford the title compound (assumed theoretical yield, 458 mg,0.815 mmol) in sufficient purity for step 2. MS (apci) m/z=562.4 (M+H).

Step 2: Preparation of4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)carbamate(458 mg, 0.815 mmol) in DCM (0.815 mL) was treated with TFA (0.0628 mL,0.815 mmol). The reaction mixture was stirred at rt for 1 h. Thereaction mixture was quenched with 4:1 DCM/IPA and water. The mixturewas washed washed successively with saturated NaHCO_(3(aq)) andsaturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (135 mg, 0.292 mmol, 35.9% yield over two steps). MS (apci)m/z=462.3 (M+H).

Intermediate P74

4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate(Example 379, 0.149 g, 0.253 mmol) in DCM (0.0163 mL) was treated withHCl in IPA (0.00769 mL, 0.253 mmol). The reaction mixture was stirred atrt then quenched with DCM and saturated Na₂CO_(3(aq)). The organicextract was dried over anhydrous MgSO_(4(s)), filtered, thenconcentrated in vacuo to afford the title compound (assumed theoreticalyield, 0.124 g, 0.253 mmol). MS (apci) m/z=489.3 (M+H).

Intermediate P75

3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P67; 256 mg, 0.608 mmol),3-Chloropicolinic acid (287 mg, 1.82 mmol), and HATU (294 mg, 1.82 mmol)in DMSO (3 mL) was added DIEA (0.74 mL, 4.25 mmol). The reaction wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with EtOAc (10 mL) and washed with water (10 mL) and4:1AcOH:water (10 mL) and then extracted with EtOAc. The organicextracts were washed with 4:1 AcOH:Water and then brine. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was diluted with THF (4 mL) and 2MNaOH (6 mL). The solution was concentrated in vacuo. The residue wasresuspended in DCM (2 mL) and purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt wasresuspended in DCM and passed through a Pl-HCO₃ resin to elute thefree-based product. The organic eluents were concentrated in vacuo andrecrystallized using DCM/Hexanes to afford the title compound (226 mg,76% yield). MS (apci) m/z=488.2 (M+H).

Intermediate P76

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide

Step 1: Preparation of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidine-4-carboxylate.To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 616.0 mg, 2.182 mmol) in DMSO (8.7 mL) was addedmethyl 4-(isobutylcarbamoyl)piperidine-4-carboxylate (1058 mg, 4.364mmol) and DIEA (0.7602 mL, 4.364 mmol). The reaction mixture was stirredat 75° C. for 16 h. After cooling to ambient temperature, the reactionmixture was diluted with EtOAc and washed successively with water andsaturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo. The residue waspurified by silica chromatography (5-95% acetone in DCM as the gradienteluent) to afford the title compound (818.0 mg, 1.621 mmol, 74% yield)in sufficient purity for step 2. MS (apci) m/z=505.3 (M+H).

Step 2: Preparation of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)-N-isobutylpiperidine-4-carboxamide.To a solution of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidine-4-carboxylate(818.0 mg, 1.621 mmol) in MeOH (16 mL) was added sodium borohydride(98%, 1532 mg, 40.1 mmol). The reaction mixture was stirred at rt for 17h. The reaction mixture was diluted with DCM and washed with water. Theorganic extract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (762 mg, 1.599 mmol,99% yield) in sufficient purity for step 3. MS (apci) m/z=477.3 (M+H).

Step 3: Preparation of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)-N-isobutylpiperidine-4-carboxamide(762.0 mg, 1.599 mmol) in DCM (16 mL) was treated with3-oxo-115-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (813.8 mg,1.919 mmol). The reaction mixture was stirred at rt for 16 h. The crudereaction mixture was concentrated in vacuo, and the residue was directlypurified by silica chromatography (5-95% EtOAc in DCM as the gradienteluent) to afford the title compound (555.2 mg, 1.170 mmol, 73.17%yield). MS (apci) m/z=475.2 (M+H).

Intermediate P77

4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 100.5 mg, 0.3560 mmol) in DMSO (3 mL) was added(4-benzylpiperidin-4-yl)methanol hydrochloride (151.5 mg, 0.6267 mmol),and cesium carbonate (812.0 mg, 2.492 mmol). The reaction mixture wasstirred at 60° C. for 24 h. After cooling to ambient temperature, thereaction mixture was diluted with DCM and washed successively with waterand saturated NH₄Cl_((aq)). The aqueous fractions were extracted withDCM, and the combined organic extracts were dried over anhydrousNa₂SO_(4(s)) then purified by silica chromatography (0-100% EtOAc inhexanes as the gradient eluent) to afford the title compound (118.2 mg,0.2528 mmol, 71.00% yield) in sufficient purity for step 2. MS (apci)m/z=468.2 (M+H).

Step 2: Preparation of4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(51.3 mg, 0.110 mmol) in DCM (1.5 mL) was treated with3-oxo-115-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (93.1 mg,0.219 mmol). The reaction mixture was stirred at rt for 1.5 h. Thereaction mixture was quenched with saturated NaHCO_(3(aq)) and extractedwith DCM. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)) and purified by silica chromatography (0-100% EtOAc inhexanes as the gradient eluent) to afford the title compound (46.7 mg,0.100 mmol, 91.4% yield) in sufficient purity for step 2. MS (apci)m/z=466.3 (M+H).

Intermediate P78

6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of2-(4-(pyridin-2-yloxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 2-Chloropyridine-5-boronic acid, pinacol ester (1.18 g,4.93 mmol) in DMSO (5.0 mL) was added DIEA (4.29 mL, 24.6 mmol) and2-(piperidin-4-yloxy)pyridine dihydrochloride (1.55 g, 6.16 mmol). Thereaction mixture was stirred at 90° C. for 72 h. After cooling toambient temperature, the reaction mixture was quenched with water andextracted with EtOAc. The combined organic extracts were successivelywashed with water and saturated NaCl_((aq)) then dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (1.19 g, 3.12 mmol, 63.3% yield) in sufficient purity for step2.

Step 2: Preparation of6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1, 800.5 mg, 3.363 mmol) in 4:1 dioxane:water (30 mL) wastreated with2-(4-(pyridin-2-yloxy)piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1410.406 mg, 3.699 mmol), tetrakis(triphenylphosphine)palladium (0)(388.6035 mg, 0.3363 mmol), and aqueous potassium carbonate (1394.277mg, 10.088 mmol). The reaction mixture was sparged with argon andstirred at 90° C. for 16 h. After cooling to ambient temperature, thereaction mixture was quenched with water and adjusted to pH 7 with 4NHCl. The mixture was extracted with 4:1 DCM:IPA, and the combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(5-95% acetone in hexanes as the gradient eluent) to afford the titlecompound (475.3 mg, 1.152 mmol, 34.3% yield). MS (apci) m/z=413.2 (M+H).

Intermediate P79

4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-bromo-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1, 1000 mg, 4.201 mmol) in DMA (21.005 L) was treatedwith potassium carbonate (1742 mg, 12.60 mmol) and4-(2-chloroethyl)morpholine (1.132 mL, 8.402 mmol). The reaction mixturewas stirred at 50° C. for 72 h. After cooling to ambient temperature,the reaction mixture was quenched with saturated NaCl_((aq)). Theresultant precipitate was isolated by filtration to afford the titlecompound (1475 mg, 4.200 mmol, 99% yield) in sufficient purity for step2. MS (apci) m/z=351 (M⁺).

Step 2: Preparation of4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-bromo-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.83 g, 1.394 mmol) in 1,4-dioxane (1000 mL) was treated with2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(373.2181 mg, 1.673 mmol), tetrakis(triphenylphosphine)palladium (0)(32.22577 mg, 0.0279 mmol), and aqueous potassium carbonate (2.092 mL,4.183 mmol). The reaction mixture was sparged with argon and stirred at90° C. for 16 h. After cooling to ambient temperature, the reactionmixture was diluted with MTBE and washed with 1N NaOH. The aqueousfractions were extracted with MTBE then adjusted to pH 4 with 4N HCl.Saturated NaCl_((aq)) was added and the aqueous mixture was extractedwith 4:1 DCM/IPA. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (0.341 g, 0.928 mmol, 66.6% yield). MS (apci) m/z=368.1(M+H).

Intermediate P80

(R)-4-(6-fluoropyridin-3-yl)-6-(2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P66, 0.2027 g, 0.78935 mmol) in THF (3.16 mL) was addedaqueous sodium hydroxide (2M, 0.40257 mL, 0.80514 mmol) dropwise. Themixture was stirred at rt for 1 h, at which time (R)-2-methyloxirane(0.33181 mL, 4.7361 mmol) was added. The reaction mixture was stirred at80° C. for 16 h. After cooling to ambient temperature, the pH wasadjusted to 5 by addition of a 10% aqueous citric acid solution. Themixture was extracted with EtOAc, then the combined organic extractswere washed successively with water and saturated NaCl_((aq)) then driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. Theresidue was purified by silica chromatography (10-90% EtOAc in hexanesas the gradient eluent) to afford the title compound (0.084 g, 0.26897mmol, 34.074% yield. MS (apci) m/z=313.1 (M+H).

Intermediate P81

tert-butyl(1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamateStep 1: Preparation of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine

To a solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5.122 g,22.56 mmol) in 1,4-dioxane (45.12 mL) was added2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.038g, 27.07 mmol), tetrakis(triphenylphosphine)palladium (0) (1.043 g,0.9023 mmol), and aqueous sodium carbonate (2M, 23.69 mL, 47.37 mmol).The reaction mixture was stirred at 80° C. for 16 h. After cooling toambient temperature, the reaction mixture was poured onto water andstirred for 4 h. The resultant precipitate was isolated by vacuumfiltration then taken up in MTBE and stirred an additional 30 min. Theprecipitate was isolated by vacuum filtration to afford the titlecompound (4.616 g, 18.98 mmol, 84.13% yield) in sufficient purity forstep 2. MS (apci) m/z=244.1 (M+H).

Step 2: Preparation of tert-butyl(1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine (2.25 g, 9.25mmol) in DMSO (18.5 mL) was added tert-butyl(4-methylpiperidin-4-yl)carbamate (2.97 g, 13.9 mmol) and DIEA (4.83 mL,27.8 mmol). The reaction mixture was stirred at 90° C. for 16 h. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and extracted with EtOAc. The combined organic extracts werewashed with saturated NaCl₍aq, dried over anhydrous Na₂SO_(4(s)), andconcentrated in vacuo. The residue was purified by silica chromatography(10-90% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (3.8 g, 8.68 mmol, 93.9% yield). MS (apci) m/z=438.3 (M+H).

Intermediate P82

1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine

A solution of tert-butyl(1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate P81, 0.500 g, 1.14 mmol) in DCM (5 mL) was treated withTFA (5 mL). The reaction mixture was stirred at rt for 1 h. The reactionmixture was concentrated in vacuo, and the residue was diluted withEtOAc and washed successively with saturated NaHCO_(3(aq)) and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),and concentrated in vacuo to afford the title compound (0.38 g, 1.13mmol, 98.5% yield). MS (apci) m/z=338.2 (M+H).

Intermediate P83

1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amineStep 1: Preparation of tert-butyl(1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of tert-butyl(1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate P81, 0.800 g, 1.83 mmol) in DCM (12.2 mL) was added NCS(0.293 g, 2.19 mmol). The reaction mixture was stirred at rt for 16 h.The reaction mixture was diluted with EtOAc and washed successively withwater and saturated NaCl_((aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), and concentrated in vacuo. The residue waspurified by silica chromatography (10-90% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.765 g, 1.62 mmol, 88.6%yield) in sufficient purity for step 2. MS (apci) m/z=472.2 (M+H).

Step 2: Preparation of1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine

A solution of tert-butyl(1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(0.765 g, 1.62 mmol) in DCM (12 mL) was treated with TFA (12 mL). Thereaction mixture was stirred at rt for 1 h. The reaction mixture wasdiluted with EtOAc and washed successively with saturated NaHCO_(3(aq))and saturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), and concentrated in vacuo to afford the title compound(0.548 g, 1.47 mmol, 90.9% yield). MS (apci) m/z=372.2 (M+H).

Intermediate P84

4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-ol Step 1: Preparation of4-bromo-3-chloro-6-methoxypyrazolo[1,5-a]pyridine

To a solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (15 g, 66.06mmol) in DCM (100 mL) was added NCS (8.821 g, 66.06 mmol). The reactionmixture was sonicated for 5 min then stirred at rt for 24 h. Thereaction mixture was diluted with Et₂O, in which it was stirred for 10min then sonicated for 2 min. The solid precipitate was isolated byvacuum filtration to afford the title compound (18.69 g, 71.47 mmol,108.2% yield) in sufficient purity for step 2. MS (apci) m/z=263.1(M+H).

Step 2: Preparation of 4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-ol

A solution of 4-bromo-3-chloro-6-methoxypyrazolo[1,5-a]pyridine (7.59 g,29.0 mmol) in DCE (290 mL) was sparged with N₂ and treated with aluminumtrichloride (11.6 g, 87.1 mmol) over the course of 5 min. The reactionmixture was stirred at 76° C. for 16 h. After cooling to ambienttemperature, the reaction mixture was quenched with DMA thenconcentrated in vacuo. The residue was taken up in water and cooled onice for 30 min. The resultant precipitate was isolated by vacuumfiltration then taken up in DMA. The solution was filtered through aplug of silica to afford the title compound as a solution in DMA(assumed quantitative yield, 7.00 g, 28.3 mmol).

Intermediate P85

1-((3-chloro-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol

Step 1: Preparation of1-((4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol

To a solution of 4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-ol(Intermediate P84, 4.2 g, 17.0 mmol) in DMA (300 mL) was added potassiumcarbonate (23.5 g, 170 mmol) and 2,2-dimethyloxirane (14.9 mL, 169.8mmol). The reaction mixture was stirred at 85° C. for 2 h. After coolingto ambient temperature, the reaction mixture was quenched with 1:1saturated NH₄Cl_((aq))/water. The solution was extracted with EtOAc. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo to afford the title compound (2.62 g, 5.74 mmol,33.8% yield) in sufficient purity for step 2. MS (apci) m/z=321.0 (M+H).

Step 2: Preparation of1-((3-chloro-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol

To a solution of1-((4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol(1.44 g, 4.51 mmol) in 1,4-dioxane was added2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.51g, 6.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.260 g, 0.225mmol), and aqueous sodium carbonate (2M, 50 mL, 100 mmol). The reactionmixture was sparged with N₂ and stirred at 90° C. for 16 h. Aftercooling to ambient temperature, the reaction mixture was quenched withwater. The solution was extracted with MTBE, and the combined organicextracts were dried over anhydrous Na₂SO_(4(s)), and concentrated invacuo. The residue was purified by silica chromatography (0-100% EtOAcin hexanes as the gradient eluent) to afford the title compound (0.37 g,1.10 mmol, 24.5% yield). MS (apci) m/z=336.1 (M+H).

Intermediate P86

3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P67, 0.253 g, 0.600 mmol) in DCM (3 mL)was added 3-chloro-5-fluoropicolinic acid (0.232 g, 1.32 mmol), HATU(0.502 g, 1.32 mmol), and DIEA (0.524 mL, 3.00 mmol). The reactionmixture was stirred at rt for 30 min. The reaction mixture was dilutedwith DCM and washed with aqueous citric acid (adjusted to pH 5). Theaqueous mixture was extracted with DCM, and the combined organicextracts were washed successively with water and saturated NaCl_((aq))then dried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. Theresidue was taken up in THF and 2M NaOH and stirred at rt for 5 min. Themixture was diluted with DCM, washed with aqueous citric acid (adjustedto pH 5), and extracted with 4:1 DCM/IPA. The combined organic extractswere washed with saturated NaCl_((aq)), dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo. The residue waspurified by C-18 reverse phase chromatography (5-95% ACN in water [+0.1%TFA] as the gradient eluent). The fractions containing the desiredproduct were diluted with 4:1 DCM/IPA and washed successively withsaturated NaHCO_(3(aq)) and saturated NaCl_((aq)). The organic extractwas dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo to afford the title compound (0.325 g, 0.578 mmol, 96.3% yield).MS (apci) m/z=506.2 (M+H).

Intermediate P87

N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P67, 255.4 mg, 0.606 mmol) in DCM (6 mL)was added benzoic acid (185.072 mg, 1.51545 mmol), HATU (576.228 mg,1.515 mmol), and DIEA (1.056 mL, 6.06 mmol). The reaction mixture wasstirred at rt for 16 h then concentrated in vacuo. The residue was takenup in THF and treated with 2M KOH_((aq)). The mixture was stirred at rtfor 1 h then adjusted to pH 4 by addition of 2M HCl. The mixture wasdiluted with water and extracted with 4:1 DCM/IPA. The combined organicextracts were washed with water then dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The residue was purified by C-18reverse phase chromatography (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werewashed with saturated NaHCO_(3(aq)) and extracted with 4:1 DCM/IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (172.5mg, 0.381 mmol, 62.9% yield). MS (apci) m/z=453.2 (M+H).

Intermediate P88

N-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

Step 1: Preparation of tert-butyl4-(2-((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate.To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(Intermediate P87, 157.2 mg, 0.3474 mmol) in DMA (3.5 mL) was addedtert-Butyl 4-(2-chloroethyl)tetrahydro-1 (2H)-pyrazinecarboxylate (172.8mg, 0.6948 mmol) and cesium carbonate (565.9 mg, 1.737 mmol). Thereaction mixture was stirred at 60° C. for 16 h. After cooling toambient temperature, the reaction mixture was diluted with EtOAc andwashed successively with water and saturated NaCl_((aq)). The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (assumed theoreticalyield, 231 mg, 0.3474 mmol) in sufficient purity for step 2. MS (apci)m/z=665.4 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide.A solution of tert-butyl4-(2-((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylatein DCM (1.75 mL) was treated with TFA (1.75 mL, 22.9 mmol). The reactionmixture was stirred at rt for 30 min then concentrated in vacuo. Theresidue was directly purified by C-18 reverse phase chromatography(5-95% ACN in water (+0.1% TFA) as the gradient eluent). The fractionscontaining the desired product were washed with saturated NaHCO_(3(aq))and extracted with 4:1 DCM/IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo toafford the title compound (111.8 mg, 0.1980 mmol, 56.99% yield over twosteps). MS (apci) m/z=565.3 (M+H).

Intermediate P89

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Example 469, 100 mg, 0.210 mmol) in DCM (2 mL) was treated with TFA (2mL). The reaction mixture was stirred at rt for 1 h. The crude reactionmixture was directly purified by silica chromatography (5-50% [MeOH+2%NH₄OH] in DCM as the gradient eluent) to afford the title compound (20mg, 0.0531 mmol, 25.3% yield). MS (apci) m/z=377.2 (M+H).

Intermediate P90

N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P67, 1.38 g, 3.2754 mmol) in DCM (6.5507mL) was added 2-Picolinic acid (1.0081 g, 8.1884 mmol), HATU (3.1135 g,8.1884 mmol), and DIEA (5.7207 mL, 32.754 mmol). The reaction mixturewas stirred at rt for 1 h then concentrated in vacuo. The residue wastaken up in THF and 2M aqueous KOH and stirred at rt for 30 min. Themixture was adjusted to pH 4 by addition of 1M HCl and extracted with4:1 DCM/IPA. The combined organic extracts were washed successively withwater and saturated NaCl_((aq)) then dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The residue was purified by C-18reverse phase chromatography (5-95% ACN in water (+0.1% TFA) as thegradient eluent). The fractions containing the desired product werediluted with 4:1 DCM/IPA and washed successively with saturatedNaHCO_(3(aq)) and saturated NaCl_((aq)). The organic extract was driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo toafford the title compound (737 mg, 1.6251 mmol, 49.616% yield). MS(apci) m/z=454.2 (M+H).

Intermediate P91

N-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl4-(2-((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate.To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P90, 120 mg, 0.265 mmol) in DMA (2.646 mL) was addedtert-Butyl 4-(2-chloroethyl)tetrahydro-1(2H)-pyrazinecarboxylate (65.8mg, 0.265 mmol) and cesium carbonate (431 mg, 1.32 mmol). The reactionmixture was stirred at 60° C. for 48 h. After cooling to ambienttemperature, the reaction mixture was diluted with 4:1 DCM/IPA andwashed successively with saturated NaHCO_(3(aq)) and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (176mg, 0.264 mmol, 99.9% yield) in sufficient purity for step 2. MS (apci)m/z=666.4 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide.A solution of tert-butyl4-(2-((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate(176 mg, 0.264 mmol) in DCM (2.643 mL) was treated with TFA (0.2 mL).The reaction mixture was stirred at rt for 1 h. The reaction mixture wasdiluted with 4:1 DCM/IPA and washed successively with saturatedNaHCO_(3(aq)), water, and saturated NaCl_((aq)). The organic extract wasdried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto afford the title compound (assumed theoretical yield, 150 mg, 0.264mmol). MS (apci) m/z=566.4 (M+H).

Intermediate P92

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicAcid Step 1: Preparation of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.9974 g, 3.533 mmol) in DMA (14.13 mL) was addedmethyl 4-methylpiperidine-4-carboxylate (1.666 g, 10.6 mmol) and TEA(2.396 mL, 17.67 mmol). The reaction mixture was stirred at 80° C. for16 h. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc and washed successively with water and brine. Theaqueous fractions were extracted with 4:1 DCM/IPA. The combined organicextracts were concentrated in vacuo, and the residue was taken up inEtOAc and washed successively with water and brine. The organic extractwas dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The residue was purified by silica chromatography (5-95% EtOAc inhexanes as the gradient eluent) to afford the title compound (436.4 mg,1.040 mmol, 29.44%) in sufficient purity for step 2. MS (apci) m/z=420.2(M+H).

Step 2: Preparation of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicAcid

A mixture of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate(776.5 mg, 1.851 mmol) in 1:1 THF/MeOH (37 mL) was treated with KOH (aq.2M) (3.7 mL, 7.4 mmol). After stirred at rt for 80 h, the reactionmixture was diluted with 1N NaOH and washed successively with MTBE andDCM. After phase-separation, the aqueous layer was acidified to ca. pH 5and extracted with 4:1 DCM/IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo toafford the title compound (470.4 mg, 1.160 mmol, 62.68% yield). MS(apci) m/z=406.2 (M+H).

Intermediate P93

4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube, a mixture of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP1, Step 6; 1.1854 g, 4.7026 mmol),2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2587g, 5.6432 mmol), Pd(PPh₃)₄ (0.1087 g, 0.094 mmol) and 2 M Na₂CO_(3(aq))(15 mL, 30 mmol) in dioxane (15 mL) was sparged with N_(2(g)). Thevessel was sealed, and the sparged mixture was stirred for 4 d at 60° C.After cooling to ambient temperature, the reaction mixture was quenchedwith water. The resultant precipitate was filtered, washed with water,and then purified by silica chromatography (0-25% MeOH in DCM) to affordthe title compound (734.6 mg, 58% yield). MS (apci), m/z=269.1 (M+H).

Intermediate P94

4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

A solution of tert-butyl((3S,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 514, 274.5 mg, 0.5909 mmol) in dioxane (3 mL) was treated with37% HCl (97 μL, 1.18 mmol), then stirred overnight at ambienttemperature. The resulting mixture was concentrated in vacuo to affordthe title compound (258 mg, 100% yield). MS (apci) m/z=365.2 (M+H).

Intermediate P95

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

A stirring, ambient temperature, solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Example 469, 807 mg, 1.69 mmol) in MeOH (3387 μL) was treated dropwisewith 12 M HCl_((aq)) (1.41 mL, 16.9 mmol). The resulting mixture wasstirred overnight at ambient temperature. The resulting thick slurry wasdiluted with MeOH (ca. 1 mL), and vacuum filtered. The solids wererinsed with MeOH (3×1 mL) and MTBE (3×10 mL), then dried in vacuo toafford the title compound (690 mg, 91% yield). MS (apci) m/z=377.2(M+H).

Intermediate P96

Tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-yl)carbamate

Tert-Butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(Intermediate P71, 100 mg, 0.2038 mmol) was added to solution ofpyrrolidine (681 μL, 0.82 mmol) and TEA (142 μL, 1.0 mmol) in DCM (1.0mL), and the mixture was stirred for 1 h at ambient temperature.Subsequently, NaBH(AcO)₃ (86.4 mg, 0.41 mmol) was added, and theresulting mixture was stirred for 2.5 h at ambient temperature thenconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% ACN:water with 0.1% TFA). Fractions containing thedesired product were combined, diluted with 4:1 DCM:iPrOH, thensequentially extracted with saturated NaHCO_(3(aq)), water and brine.The organic extracts were dried over anhydrous Na₂SO_(4(s)), filtered,and concentrated in vacuo to cleanly afford the title compound (40 mg,36% yield). MS (apci) m/z=546.3 (M+H).

Intermediate P97

4-(6-(4-amino-4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-yl)carbamate(Intermediate P96; 40 mg, 0.073 mmol) in DCE (4.7 μL) and TFA (5.6 μL,0.073 mmol) was stirred for 90 min at ambient temperature. The resultingmixture was diluted with 4:1 DCM:iPrOH, then sequentially extracted withsaturated NaHCO_(3(aq)), water and brine. The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto cleanly afford the title compound (30 mg, 92% yield). MS (apci)m/z=446.3 (M+H).

Intermediate P98

4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate(Example 379, 171.2 mg, 0.2908 mmol) in dioxane (5.0 mL) was treatedwith 12 M HCl_((aq)) (23.88 μL, 0.2908 mmol). The resulting mixture wasstirred for 45 min at ambient temperature before concentrating themixture in vacuo to cleanly afford the title compound (205.5 mg,quantitative yield). MS (apci) m/z=489.3 (M+H).

Intermediate P99

tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(Intermediate P71, 278 mg, 0.567 mmol) and (S)-1,2-dimethylpiperazine(Intermediate P93; 270 mg, 2.36 mmol) in DCE (5 mL) was stirred for 30min at ambient temperature before adding NaBH(AcO)₃ (480.4 mg, 2.267mmol). The resulting mixture was stirred overnight at ambienttemperature, then concentrated in vacuo. The residue was suspended in4:1 DCM:iPrOH, and extracted sequentially with saturated NaHCO_(3(aq))(2×) and brine. The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (using 0-15% [MeOH with 1% NH₄OH] inDCM as the gradient eluent) to cleanly afford the title compound (133mg, 40% yield). MS (apci) m/z=589.3 (M+H).

Intermediate P100

methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(3-methylbutanamido)piperidine-4-carboxylate

A solution of methyl4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate(Step1, Intermediate P70, 500 mg, 1.19 mmol) in DCM (5 mL) was treatedwith DIEA (415.4 μL, 2.378 mmol), then stirred for 10 min at 0° C. Thecold solution was treated dropwise with isovaleryl chloride (174 μL,1.43 mmol). The resulting mixture was stirred for 1 h at 0° C. Themixture was diluted with 4:1 DCM:iPrOH, and extracted with saturatedNaHCO_(3(aq)) (2×). After back extracting the aqueous extracts with DCM,all organic extracts were combined, dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to cleanly afford the title compound(943.9 mg, 79% yield). MS (apci) m/z=505.2 (M+H).

Intermediate P101

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-3-methylbutanamide

A solution of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(3-methylbutanamido)piperidine-4-carboxylate(Intermediate P93; 476.3 mg, 0.9439 mmol) in THF (5 mL) was stirred for20 min at 0° C. The cold solution was treated with LiBH₄ (82.24 mg,3.776 mmol). The resulting mixture was stirred overnight at ambienttemperature, then concentrated in vacuo. The residue was dissolved inEtOAc, and extracted with brine (3×). After back extracting the aqueousextracts with EtOAc, the organic extracts were combined, dried overanhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. The crudeproduct was purified by silica chromatography (using 40-100% EtOAc inHexanes as the gradient eluent) to cleanly afford the title compound(95.7 mg, 21% yield). MS (apci) m/z=477.25 (M+H).

Intermediate P102

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-3-methylbutanamide

A solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-3-methylbutanamide(Intermediate P101; 95.7 mg, 0.201 mmol) in DCM (2 mL) was treated withDMP (170 mg, 0.402 mmol). The resulting mixture was stirred for 1.5 h atambient temperature. The reaction mixture was diluted with DCM, andextracted with saturated NaHCO_(3(aq)). After back extracting theaqueous extracts with DCM, the organic extracts were combined, driedover anhydrous Na₂SO_(4(s)), and filtered. The filtrate was purifieddirectly by silica chromatography (using 20-80% EtOAc in Hexanes as thegradient eluent) to cleanly afford the title compound (41.0 mg, 43%yield). MS (apci) m/z=475.2 (M+H).

Intermediate P103

methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((isopropoxycarbonyl)amino)piperidine-4-carboxylate

A solution of methyl4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate(step1, Intermediate P70, 334.8 mg, 0.7962 mmol) in DCM (51.23 μL) wastreated with DIEA (278.1 μL, 1.592 mmol), then stirred for 10 min at 0°C. The cold solution was treated dropwise with isopropylcarbonochloridate (955.5 μL, 0.9555 mmol). The resulting mixture wasstirred for 40 min at 0° C., then overnight at ambient temperature. Themixture was purified directly by silica chromatography (using 30-70%EtOAc in Hexanes as the gradient eluent) to cleanly afford the titlecompound (323.5 mg, 80% yield). MS (apci) m/z=507.15 (M+H).

Intermediate P104

Isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate

A solution of methyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((isopropoxycarbonyl)amino)piperidine-4-carboxylate(Intermediate P103; 323.5 mg, 0.6386 mmol) in THF (3 mL) was stirred for20 min at 0° C. The cold solution was treated with LiBH₄ (55.64 mg,2.554 mmol). The resulting mixture was stirred overnight at ambienttemperature, then concentrated in vacuo. The residue was dissolved inDCM, and extracted with brine. The organic extracts were purifieddirectly by silica chromatography (using 30-100% EtOAc in Hexanes as thegradient eluent) to cleanly afford the title compound (171.7 mg, 56%yield). MS (apci) m/z=479.2 (M+H).

Intermediate P105

Isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate

A solution of isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate(Intermediate P104; 171 mg, 0.357 mmol) in DCM (1 mL) was treated withDMP (303.1 mg, 0.7147 mmol). The resulting mixture was stirred overnightat ambient temperature. The reaction mixture was diluted with DCM, andextracted sequentially with water and brine. After back extracting theaqueous extracts with DCM, the organic extracts were combined, driedover anhydrous Na₂SO_(4(s)), and filtered. The filtrate was purifieddirectly by silica chromatography (using 20-80% EtOAc in Hexanes as thegradient eluent) to cleanly afford the title compound (167.4 mg, 98%yield). MS (apci) m/z=477.2 (M+H).

Intermediate P106

4-(6-(4-amino-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 4-(pyridin-2-ylmethyl)piperidin-4-aminebis(2,2,2-trifluoroacetate) (Intermediate R41; 287.5 mg, 0.6856 mmol) inDMF (2 mL) was treated with6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 176 mg, 0.624 mmol), K₂CO_(3(s)) (431 mg, 3.12 mmol)was stirred overnight at 70° C. The mixture was cooled to ambienttemperature, diluted with water (50 mL) and extracted with DCM (3×20mL). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The crude residue was purified bysilica chromatography (0-15% MeOH in DCM) to afford the title compound(73 mg, 26% yield). MS (apci) m/z=454 (M+H).

Intermediate P107

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-morpholinoethoxy)methyl)piperidine-4-carboxylicacid Dihydrochloride

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-4-carboxylicacid (Intermediate P156; 30 mg, 0.071 mmol) in DMF (1 mL) was treatedwith NaH (60 wt. % in mineral oil; 8.5 mg, 0.21 mmol). The suspensionwas stirred for 5 min at 50° C., then treated with4-(2-chloroethyl)morpholine (32 mg, 0.21 mmol). The resulting mixturewas stirred for 15 h at 50° C. before introducing additional NaH (2equivalents) and 4-(2-chloroethyl)morpholine (3 equivalents). Themixture was stirred for 4 h at 70° C. After cooling to ambienttemperature, the mixture was concentrated in vacuo, and diluted withMeOH (2 mL). The methanolic mixture was treated with 2 M NaOH_((aq)) (2mL), and stirred for 15 h at 50° C. After cooling to ambienttemperature, the reaction mixture was concentrated in vacuo, andpurified by C18 reverse phase chromatography (5-95% acetonitrile/water).Fractions containing the desired product were combined, concentrated invacuo, and then treated with 4 M HCl in dioxane. The HCl mixture wasconcentrated in vacuo to afford the title compound (25 mg, 58% yield).MS (apci) m/z=535.2 (M+H).

Intermediate P108

Ethyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-(dimethylamino)ethoxy)methyl)piperidine-4-carboxylateDihydrochloride

A solution of ethyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-4-carboxylate(Example 701; 30 mg, 0.067 mmol) in DMF (1 mL) was treated with NaH (60wt. % in mineral oil; 21 mg, 0.53 mmol). The suspension was stirred for5 min at 50° C., then treated with 2-chloro-N,N-dimethylethan-1-aminehydrochloride (38 mg, 0.27 mmol). The resulting mixture was stirred for1 h at ambient temperature then for 15 h at 50° C. After cooling toambient temperature, the mixture was diluted with water and extractedwith DCM. The organic extracts were purified by C18 reverse phasechromatography (5-95% ACN:water with 0.1% TFA). Fractions containing thedesired product were combined, passed through a basic resin(Stratospheres Pl-HCO3) rinsing with 1 M HCl_((aq)), then concentratedin vacuo to afford the title compound (6 mg, 17% yield). MS (apci)m/z=521.3 (M+H).

Intermediate P109

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-(dimethylamino)ethoxy)methyl)piperidine-4-carboxylicacid Dihydrochloride

A mixture of ethyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-(dimethylamino)ethoxy)methyl)piperidine-4-carboxylatedihydrochloride (8 mg, 0.02 mmol), 2 M NaOH_((aq)) (1 mL) and EtOH (1mL) was stirred for 60 h at ambient temperature. After concentrating themixture in vacuo, the residue was purified by C18 reverse phasechromatography (5-95% ACN:water with 0.1% TFA). Fractions containing thedesired product were combined, concentrated in vacuo and then treatedwith 4 M HCl in dioxane. The HCl mixture was concentrated in vacuo toafford the title compound (4 mg, 53% yield). MS (apci) m/z=493.4 (M+H).

Intermediate P110

6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure vessel, a solution of4-bromo-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P5,1.37 g, 5.15 mmol) in dioxane (52 mL) was treated withbis(pinacolato)diboron (3.92 g, 15.4 mmol), PdCl₂(dppf).CH₂Cl₂ (0.420 g,0.515 mmol), and KOAc (1.52 g, 15.4 mmol), then sparged with Ar_((g)).The vessel was sealed, and the mixture was stirred for 16 h at 90° C.After cooling to ambient temperature, the reaction mixture was dilutedwith EtOAc, and washed sequentially with water (2×) and brine (1×). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The crude residue was purified by silicachromatography (using 5-75% Hexanes-EtOAc as the gradient eluent) tocleanly afford the title compound (1.31 g, 81% yield). MS (apci)m/z=314.2 (M+H).

Intermediate P111

methyl4-((tert-butoxycarbonyl)amino)-1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-4-carboxylate

In a pressure vessel, a solution of methyl1-(4-bromophenyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate(Intermediate R43; 377.4 mg, 0.9131 mmol) in dioxane (77 mL) was treatedwith6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P110; 314.5 mg, 1.004 mmol), Pd(PPh₃)₄ (105.5 mg, 0.09131mmol) and K₂CO_(3(s)) (378.6 mg, 2.739 mmol), then sparged withAr_((g)). The vessel was sealed, and stirred for 16 h at 90° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc, and washed sequentially with water (2×) and brine (1×). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The crude residue was purified by silicachromatography (using 5-95% Hexanes-EtOAc as the gradient eluent) tocleanly afford the title compound (173.0 mg, 36% yield). MS (apci)m/z=520.3 (M+H).

Intermediate P112

tert-butyl(1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-(hydroxymethyl)piperidin-4-yl)carbamate

A solution of methyl4-((tert-butoxycarbonyl)amino)-1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-4-carboxylate(Intermediate P111; 173.0 mg, 0.3329 mmol) in THF (3.3 mL) was stirredat 0° C., then treated with LiBH₄ (36.26 mg, 1.665 mmol). The resultingmixture was stirred overnight at ambient temperature, then diluted with10% citric acid solution, and extracted with EtOAc (2×). The combinedorganic extracts were washed sequentially with water (1×) and brine(1×), dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The crude product was purified by silica chromatography (using5-95% Hexanes-Acetone as the gradient eluent) to cleanly afford thetitle compound (64 mg, 39% yield). MS (apci) m/z=492.3 (M+H).

Intermediate P113

tert-butyl(1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-formylpiperidin-4-yl)carbamate

A solution of tert-butyl(1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-(hydroxymethyl)piperidin-4-yl)carbamate(Intermediate P112; 64.0 mg, 0.130 mmol) in DCM (1.3 mL) was treatedwith DMP (66.3 mg, 0.156 mmol). The resulting mixture was stirred for 16h at ambient temperature. The reaction mixture was concentrated invacuo. The crude residue was purified directly by silica chromatography(using 5-95% Hexanes-EtOAc as the gradient eluent) to cleanly afford thetitle compound (41.8 mg, 66% yield). MS (apci) m/z=490.3 (M+H).

Intermediate P114

4-(4-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)phenyl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl(1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate.A solution of dimethylamine hydrochloride (34.8 mg, 0.427 mmol) in DCM(1.7 mL) was treated with TEA (59.5 μL, 0.427 mmol). The mixture wasstirred at for 15 minutes at ambient temperature before tert-butyl(1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-formylpiperidin-4-yl)carbamate(Intermediate P113; 41.8 mg, 0.0854 mmol) was added. The resultingmixture was stirred for 15 min at ambient temperature, then NaBH(AcO)₃(90.5 mg, 0.427 mmol) was added. The reaction mixture was stirred for 16h at room temperature. The mixture was diluted with 4:1 DCM:iPrOH, andwashed with water. The organic extracts were washed sequentially withwater (1×) and brine (1×), dried over anhydrous Na₂SO_(4(s)), filtered,and concentrated in vacuo afford the title compound which was carrieddirectly into Step 2 (0.0854 mmol, quantitative yield was assumed). MS(apci) m/z=519.3 (M+H).

Step 2: Preparation of4-(4-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)phenyl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Crude tert-butyl(1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate(Step 1, 0.0854 mmol) was 1:1 DCM:TFA (2.0 mL), and stirred for 30 minat ambient temperature before concentrating the mixture in vacuo. Thecrude residue was suspended in 4:1 DCM:iPrOH, and extracted withsaturated NaHCO_(3(aq)) (2×). The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (35.7 mg, quantitative yield). MS (apci) m/z=419.3 (M+H).

Intermediate P115

3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yldimethylcarbamate

A solution of4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P66, 145.9 mg, 0.5739 mmol) and DIEA (200.5 μL, 1.148mmol) in DCM (2.0 mL) was treated with dimethylcarbamic chloride (92.57mg, 0.8609 mmol), then stirred overnight at ambient temperature. Thereaction mixture was washed with water. The organic extracts wereseparated, and purified directly by silica chromatography (using 20-80%Hexanes/EtOAc as the gradient eluent) to cleanly afford the titlecompound (158.4 mg, 85% yield). MS (apci) m/z=326.1 (M+H).

Intermediate P116

6-(2-(1H-imidazol-1-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P66, 100.3 mg, 0.3945 mmol),1-(2-chloroethyl)-1H-imidazole hydrochloride (197.7 mg, 1.184 mmol) andCs₂CO_(3(s)) (1.285 g, 3.945 mmol) in DMA (2.0 mL) was stirred overnightat 60° C. After cooling to ambient temperature, the reaction mixture wasdiluted with water and washed sequentially with DCM (4×) and 4:1DCM:iPrOH. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), and filtered. The filtrate was purified directly by silicachromatography (using 0-25% DCM/MeOH with 1% NH₄OH as the gradienteluent) to cleanly afford the title compound (158.4 mg, 85% yield). MS(apci) m/z=349.10 (M+H).

Intermediate P117

4-(6-fluoropyridin-3-yl)-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P66, 103.6 mg, 0.4075 mmol),4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (199.7 mg, 1.196mmol) and Cs₂CO_(3(s)) (1.328 g, 4.075 mmol) in DMA (2.0 mL) was stirredfor 1 d at 60° C., then for an additional 1 d at 110° C. After coolingto ambient temperature, the reaction mixture was acidified with 2 MHCl_((aq)), and purified directly by C18 reverse phase chromatography(using 0-70% water/ACN with 0.1% TFA as the gradient eluent). Fractionscontaining the desired product were combined, partially concentrated invacuo to remove the ACN, then partitioned between saturatedNaHCO_(3(aq)) and 4:1 DCM:iPrOH. The biphasic mixture was extracted withadditional 4:1 DCM:iPrOH (3×). The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (26.0 mg, 18% yield). MS (apci) m/z=349.10(M+H).

Intermediate P118

tert-butyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P79, 485 mg, 1.32 mmol) in DMSO (2.64 mL) was treated withtert-butyl 4-methylpiperidin-4-ylcarbamate (396 mg, 1.85 mmol) and DIEA(690 μL, 3.96 mmol) was stirred overnight at 90° C. After cooling toambient temperature, the reaction mixture was poured into water (200mL), and acidified to pH 5 with 10% citric acid. After stirring for 15min at ambient temperature, the aqueous suspension was vacuum filtered.The solids were purified by silica chromatography (5-95%: 10% MeOH inDCM with 1% NH₄OH/DCM) to afford the title compound (390 mg, 53% yield).MS (apci) m/z=562.3 (M+H).

Intermediate P119

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

A solution of tert-butyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate P118; 390 mg, 0.694 mmol) was suspended in DCM (3 mL) andtreated with TFA (1.0 mL). The resulting mixture was stirred for 2 h atambient temperature before concentrating the mixture in vacuo to affordthe title compound as a TFA salt (229.6 mg, 48% yield). MS: m/z=462.3(M+H).

Intermediate P120

methyl1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate

A solution of4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P79, 305.6 mg, 0.8318 mmol) in DMF (3.327 mL) was treatedwith methyl 4-methylpiperidine-4-carboxylate (350.3 μL, 2.495 mmol) andTEA (564.2 μL, 4.159 mmol) was stirred overnight at 90° C. After coolingto ambient temperature, the reaction mixture diluted with EtOAc, andwashed sequentially with water (3×) and brine (1×). After washing theaqueous extracts with 4:1 DCM:iPrOH, the DCM:iPrOH extracts wereconcentrated in vacuo. The residue was dissolved in EtOAc, thenextracted with water (3×) and brine (1×) before combining with theoriginal EtOAc extracts. The combined EtOAc extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The cruderesidue was purified by silica chromatography (using 5-95% Hexanes:EtOAcas the gradient eluent) to afford the title compound (354 mg, 84%yield). MS (apci) m/z=505.3 (M+H).

Intermediate P121

1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicAcid

A solution of methyl1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate(Intermediate P120; 354 mg, 0.702 mmol) in 1:1 THF:MeOH (3.0 mL) wastreated with 2.0 M KOH_((aq)) (3.5 mL, 7.02 mmol), then stirred for 64 hat ambient temperature. The resulting mixture was diluted with waterthen treated with 1.0 M NaOH_((aq)) to bring the mixture to pH 14. Themixture was extracted with 4:1 DCM:iPrOH (3×). The aqueous extracts wereacidified (ca. pH 4) with the addition of 1.0 M HCl_((aq)), thenextracted with 4:1 DCM:iPrOH (3×). The organic extracts from the acidextraction were combined, dried over anhydrous Na₂SO_(4(s)), filtered,and concentrated in vacuo to afford the title compound (298 mg, 87%yield). MS (apci) m/z=505.3 (M+H).

Intermediate P122

6-(2-morpholinoethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure vessel, a mixture of4-bromo-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P79, step 1, 426 mg, 1.21 mmol), bis(pinacolato)diboron(3.08 g, 12.1 mmol), PdCl₂(dppf).CH₂Cl₂ (89 mg, 0.121 mmol) and KOAc(595 mg, 6.06 mmol) in dioxane (10 mL) was sparged with N_(2(g)), for 1min. The vessel was sealed, and the mixture was stirred overnight at 90°C. After cooling to ambient temperature, the reaction mixture wasdiluted with DCM (15 mL), and filtered through Celite®. The filtrate wasconcentrated in vacuo, and the residue was purified by silicachromatography (using 0-100% Hexanes/Acetone as the gradient eluent) toafford the title compound (185 mg, 38% yield). MS (apci) m/z=317 (M+H).

Intermediate P123

tert-butyl(1-(6-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

In a pressure tube, a suspension of6-(2-morpholinoethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P122; 24 mg, 0.061 mmol) in 3:1 dioxane:water (0.4 mL) wastreated with Cs₂CO_(3(s)) (60 mg, 0.18 mmol) and tert-butyl(1-(6-bromopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (IntermediateR45; 25 mg, 0.068 mmol), then sparged with N_(2(g)) for 5 min. Theresulting mixture was treated with X-phos (150.9 mg, 0.3165 mmol) andPd₂(dba)₃ (144.9 mg, 0.1582 mmol), then sparged with N_(2(g)). Aftersealing the vessel, the reaction mixture was stirred for 20 h at 80° C.After cooling to ambient temperature, the resulting suspension wasdiluted with water (25 mL) and extracted with DCM (2×25 mL). Thecombined organic extracts were dried over anhydrous MgSO_(4(s)),filtered and concentrated in vacuo. The crude residue was purified bysilica chromatography (using 0-90% Acetone/Hexanes as the gradienteluent) to cleanly afford the title compound (5.4 mg, 16% yield). MS(apci) m/z=562.3 (M+H).

Intermediate P124

4-(5-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

A solution of tert-butyl(1-(6-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate P123; 5.0 mg, 0.0089 mmol) in DCM (500 μL) was treatedwith 5-6 N HCl in iPrOH (534 μL, 2.67 mmol), and stirred for 30 min atambient temperature. The resulting mixture was concentrated in vacuo,azeotroping with Et₂O, and then dried under high vacuum to afford thetitle compound (4.8 mg, quantitative yield). MS (apci) m/z=462.3 (M+H).

Intermediate P125

4-bromo-6-(2-chloroethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1, 574 mg, 2.41 mmol) in DMF (2.41 mL) was treatedsequentially with anhydrous K₂CO_(3(s)) (1.67 g, 12.1 mmol) and1-chloro-2-iodoethane (221 μL, 2.41 mmol), then stirred for 48 h atambient temperature. Subsequently, additional 1-chloro-2-iodoethane (221μL, 2.41 mmol) was introduced, and the mixture was stirred for anadditional 60 h at ambient temperature. The reaction mixture waspartitioned between DCM and water. The resulting emulsion was filtered,and the biphasic filtrate was separated. After back extracting theaqueous extracts with 4:1 DCM:iPrOH (3×), all organic extracts werecombined, dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo. The crude residue was purified by silica chromatography (using0-100% EtOAc/Hexanes as the gradient eluent) to cleanly afford the titlecompound (331 mg, 46% yield). ¹H NMR (CDCl₃) δ 8.19 (s, 1H), 8.11 (d,1H), 7.47 (d, 1H), 4.24 (t, 2H), 3.84 (t, 2H).

Intermediate P126

6-(2-(azetidin-1-yl)ethoxy)-4-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-bromo-6-(2-chloroethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P125; 77 mg, 0.256 mmol) in DMF (256 μL) was treatedsequentially with DIEA (447 μl, 2.56 mmol) and azetidine (43.9 mg, 0.769mmol). The resulting mixture was stirred overnight at 60° C. Aftercooling to ambient temperature, the reaction mixture was diluted withwater, and the resultant suspension was filtered. The solids werecollected, and dried under high vacuum to cleanly afford the titlecompound (42 mg, 51% yield). MS (apci) m/z=321 (M+H).

Intermediate P127

(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)boronic Acid

In a pressure vessel, a mixture of4-bromo-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P79, step 1, 200 mg, 0.3360 mmol), bis(pinacolato)diboron(1.446 g, 5.694 mmol), PdCl₂(dppf).CH₂Cl₂ (46.4 mg, 0.0570 mmol) andKOAc (167.7 mg, 1.709 mmol) in dioxane (3.36 mL) was sparged withAr_((g)), for 10 min. The vessel was sealed, and the mixture was stirredovernight at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM, and filtered through GF/F paper. Thefiltrate was concentrated in vacuo, and the residue was purified bysilica chromatography (using 0-20% MeOH in DCM with 2% NH₄OH as thegradient eluent). The purified residue was dissolved in DCM (2 mL) andtriturated with Et₂O (5 mL). The resulting suspension was filtered, andthe solids were isolated to afford the title compound (60 mg, 56%yield). MS (apci) m/z=317.1 (M+H).

Intermediate P128

tert-butyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate

In a pressure tube, a mixture of(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)boronic acid(Intermediate P127; 215 mg, 0.680 mmol), tert-butyl(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (IntermediateR46; 37.6 mg, 0.0991 mmol), X-phos (64.8 mg, 0.136 mmol) and Pd₂(dba)₃(31.1 mg, 0.0340 mmol) in dioxane (3.40 mL) was treated with 2 MK₃PO_(4(aq)) (1.02 mL, 2.04 mmol). The mixture was sparged with Ar_((g))for 10 min, and then the vessel was sealed. The reaction mixture wasstirred overnight at 80° C. After cooling to ambient temperature, thereaction mixture was diluted with DCM and extracted sequentially withwater and brine. The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The crude residue waspurified by silica chromatography (using 0-100% EtOAc/Hexanes followedby 0-10% MeOH in DCM with 0.1% NH₄OH as the gradient eluent) to cleanlyafford the title compound (102 mg, 27% yield). MS (apci) m/z=563.3(M+H).

Intermediate P129

4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

A solution tert-butyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate P128; 102 mg, 0.181 mmol) in DCM (1 mL) and TFA (1.4 mL,18.1 mmol) was stirred for 2.5 h at ambient temperature. The reactionmixture was concentrated in vacuo. The residue was diluted with DCM,then triturated with Et₂O, and concentrated in vacuo (repeat trituration3×). The solid residue was dried under high vacuum to afford the titlecompound (125 mg, 100% yield). MS (apci) m/z=463.3 (M+H).

Intermediate P130

tert-butyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamateStep 1: Preparation of(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrimidin-5-yl)boronicAcid

In a pressure vessel, a mixture of tert-butyl(4-methylpiperidin-4-yl)carbamate (0.23 g, 1.1 mmol),2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.2g, 0.89 mmol) and K₂CO_(3(s)) (0.62 g, 4.5 mmol) was combined in dioxane(8.9 mL), and the vessel was sealed. The reaction mixture was stirredovernight at 60° C. After cooling to ambient temperature, the reactionmixture was directly used for the next step assuming quantitative yield.MS (apci) m/z=337.2 (M+H).

Step 2: Preparation of tert-butyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate.In a sealed vessel, a solution of(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrimidin-5-yl)boronicacid (300 mg, 0.892 mmol) and K₂CO_(3(s)) (617 mg, 4.46 mmol) in dioxane(8.92 mL) was treated with water (0.892 mL),4-bromo-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P79, step 1, 313 mg, 0.892 mmol) and Pd(PPh₃)₄ (103 mg,0.0892 mmol), then sparged with Ar_((g)). After sealing the vessel, thereaction mixture was stirred for 16 h at 80° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc, and washedwith brine (3×). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The crude residue waspurified by silica chromatography (using 0-20% MeOH in EtOAc as thegradient eluent) to cleanly afford the title compound (243 mg, 36%yield). MS (apci) m/z=563.4 (M+H).

Intermediate P131

4-(2-(4-amino-4-methylpiperidin-1-yl)pyrimidin-5-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

A solution tert-butyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate P130; 91 mg, 0.147 mmol in DCM (2 mL) and TFA (2 mL, 26mmol) was stirred overnight at ambient temperature, then treated withadditional TFA (2 mL). The reaction mixture was stirred for 4 h at 40°C., and 60 h at ambient temperature before concentrating in vacuo. Theresidue was dried under high vacuum for 3 h to afford the title compound(101.52 mg, quantitative yield). MS (apci) m/z=463.3 (M+H).

Intermediate P132

tert-butyl4-(2-((4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate

A mixture of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1, 200 mg, 0.840 mmol) in DMA (4.20 mL) was treatedsequentially with K₂CO_(3(s)) (348 mg, 12.1 mmol) and tert-butyl4-(2-bromoethyl)piperazine-1-carboxylate (493 mg, 1.68 mmol), thenstirred for 3 h at 60° C. After cooling to ambient temperature, themixture was diluted with brine. The resulting suspension was filtered,and the solids were rinsed with water (5×). The solids the werecollected, dissolved in DCM and concentrated in vacuo to cleanly affordthe title compound (239 mg, 63% yield). MS (apci) m/z=452.0 (M+H).

The compounds in Table bbb were prepared using a similar procedure tothat used for the synthesis of tert-butyl4-(2-((4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate(Intermediate P132) replacing tert-butyl4-(2-bromoethyl)piperazine-1-carboxylate with (1.0-2.0 equivalents) ofthe appropriate alkyl halide (or alkyl halide salt). Reactions wereconducted between 50-60° C., and monitored for completion by LCMS, andreaction durations were adjusted accordingly. Where noted (*) anadditional work up step was required, involving an aqueous work up ofthe filtrate (or the reaction mixture) using DCM, water and brine,followed by a chromatographic purification of the organics from theextraction using an appropriate gradient eluent.

TABLE bbb Interme- diate # Structure Chemical Name Analytical P133

tert-butyl 3-(((4-bromo-3- cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3- fluoropyrrolidine-1-carboxylate ¹H NMR (CDCl₃) δ 8.20(s, 1H), 8.14 (d, 1H), 7.49 (br m, 1H), 4.19 m, 2H), 3.46- 3.82 (m, 6H),2.28 (m, 1H), 2.09 (m, 1H) 1.46 (s, 12H). P134

4-bromo-6-(2-(pyrrolidin-1- yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile MS (apci) m/z 337 (M + 2, with Br pattern)P135*

tert-butyl 3-(((4-bromo-3- cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3- fluoroazetidine-1-carboxylate ¹H NMR (CDCl₃) δ 8.83(d, 1H), 8.67 (s, 1H), 7.91 (d, 1H), 4.49-4.55 (d, 2H), 3.91- 4.15 (m,4H), 1.39 (s, 9H) P136*

tert-butyl (R)-2-(((4-bromo-3- cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4- carboxylate ¹H NMR (CDCl₃) 8.21 (s, 1H),8.17(d, 1H), 7.50(d, 1H), 3.78-4.42(m, 9H), 1.48(s, 9H) P137*

4-bromo-6-((1-methyl-1H- imidazol-4- yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile MS (apci) m/z 334 (M + 2, with Br pattern)P138*

tert-butyl (S)-2-(((4-bromo-3- cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4- carboxylate ¹H NMR (CDCl₃)8.23 (d, 1H), 8.21(s, 1H), 7.51 (d, 1H), 3.52- 4.14 (m, 9H), 1.48 (s, 9H) P139*

tert-butyl(2-((4-bromo-3- cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate ¹H NMR (CDCl₃) δ 8.19 (s, 1H), 8.10 (d, 1H), 7.43(d, 1H), 4.91 (s, 1H), 4.03 (t, 2H), 3.56 (t, 2H), 1.44 (s, 9H)

Intermediate P140

tert-butyl(R)-2-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate

In a pressure vessel, a mixture of tert-butyl(R)-2-(((4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P136; 367 mg, 0.839 mmol), bis(pinacolato)diboron (2.131g, 8.39 mmol), PdCl₂(dppf).CH₂Cl₂ (68.4 mg, 0.0839 mmol) and KOAc (412mg, 4.20 mmol) in dioxane (8.393 mL) was sparged with Ar_((g)), for 10min. The vessel was sealed, and the mixture was stirred overnight at 80°C. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc, and filtered through GF/F paper. The filtrate wasconcentrated in vacuo, and the residue was triturated with pentane. Thepentane suspension was filtered, and the solids were isolated to affordthe title compound (304 mg, 75% yield). ¹HNMR (CDCl₃) δ 8.19 (s, 1H),7.70 (s, 1H), 7.25 (s, 1H), 3.80-4.12 (m, 6H), 3.52-3.75 (m, 3H), 1.57(s, 9H), 1.49 (s, 12H).

The compounds in Table ccc were prepared using a similar procedure tothat used for the synthesis of tert-butyl(R)-2-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P140) replacing tert-butyl(R)-2-(((4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P136) with the appropriate4-bromo-6-alkoxypyrazolo[1,5-a]pyridine-3-carbonitrile from Table bbb(or the synthetic intermediate referenced therein). Reactions weremonitored for completion by LCMS, and reaction durations were adjustedaccordingly. Work ups were conducted with either DCM or EtOAc, and wherenoted (*) either a second trituration from pentane or a chromatographicpurification using an appropriate gradient eluent (in place of thetrituration) was required.

TABLE ccc Interme- diate # Structure Chemical Name Analytical P141*

tert-butyl 4-(2-((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-6- yl)oxy)ethyl)piperazine-1-carboxylate MS (apci) m/z 416.2 (M-Pinacol) ¹H NMR (CDCl₃) δ 8.19 (s,1H), 8.16 (d, 1H), 7.65 (d, 1H), 4.10 (t, 2H), 3.45 (t, 4H), 2.83 (t,2H), 2.51 (t, 4H) 1.45 (s, 9H), 1.41 (s, 12H). P142

tert-butyl 3-(((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-6-yl)oxy)methyl)-3-fluoropyrrolidine-1-carboxylate ¹H NMR (CDCl₃) δ 8.20 (m, 2H), 7.67 (s,1H), 4.17 (m, 2H), 3.49-3.84 (m, 5H), 2.00- 2.35 (m, 3H), 1.45 (s, 9H),1.42 (s, 12H). P143*

6-(2-(pyrrolidin-1-yl)ethoxy)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile MS (apci) m/z301.1 (M-Pinacol) P144

tert-butyl 3-(((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate ¹H NMR (CDCl₃) δ 8.21 (d, 1H), 8.19 (s,1H), 7.69 (d, 1H), 4.11-4.39 (m, 6H), 1.45 (s, 9H), 1.41 (s, 12H) P145

6-((1-methyl-1H-imidazol-4- yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ¹H NMR (CDCl₃) δ 8.36 (s, 1H), 8.18 (d, 1H), 7.45 (d, 1H),7.01 (d, 1H), 6.97 (s, 1H), 5.05 (s, 2H), 3.71 (s, 3H), 1.26 (s, 12H)P146

tert-butyl (S)-2-(((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-6- yl)oxy)methyl)morpholine-4-carboxylate ¹H NMR (CDCl₃) δ 8.20 (d, 1H), 7.69 (s, 1H), 7.26 (d, 1H),3.54-4.25 (m, 9H), 1.48 (s, 9H), !.42 (s, 12H) P147

tert-butyl (2-((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-6- yl)oxy)ethyl)carbamate MS(apci) m/z 347.1 (M-pinacol)

Intermediate P148

Tert-butyl(R)-2-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate

In a pressure tube, a mixture of tert-butyl(R)-2-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P140; 96 mg, 0.198 mmol),2-chloro-N-(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Intermediate R48; 37.6 mg, 0.0991 mmol), 2 M K₃PO_(4(aq)) (149 μL,0.297 mmol), X-phos (9.45 mg, 0.0198 mmol) and Pd₂(dba)₃ (4.54 mg,0.00495 mmol) in dioxane (1.0 mL) was sparged with Ar_((g)) for 10 min,and then the vessel was sealed. The reaction mixture was stirredovernight at 80° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM, and extracted sequentially with water (3×)and brine (1×). The organic extracts were concentrated in vacuo, andpurified by silica chromatography (using 0-100% EtOAc/Hexanes as thegradient eluent) to cleanly afford the title compound (40.3 mg, 58%yield). MS (apci) m/z=701.2 (M+H).

The compounds in Table ddd were prepared using a similar procedure tothat used for the synthesis of tert-butyl(R)-2-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P148) replacing of tert-butyl(R)-2-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P140) with the appropriate boronate ester from Table ccc(or the synthetic intermediate referenced therein). Reactions weremonitored for completion by LCMS, and reaction durations were adjustedaccordingly. The title compounds were isolated following achromatographic purification using an appropriate eluent.

TABLE ddd Interme- MS (apci) diate # Structure Chemical Name m/z P149

tert-butyl 3-(((4- (5-(4-(2-chloro-6- methylbenzamido)- 4-methylpiperidin-1- yl)pyrazin-2-yl)-3- cyanopyrazolo[1,5- a]pyridin-6-yl)oxy)methyl)-3- fluoropyrrolidine- 1-carboxylate 703.20 (M + H) P150

tert-butyl (S)-2- (((4-(5-(4-(2- chloro-6- methylbenzamido)- 4-methylpiperidin-1- yl)pyrazin-2-yl)-3- cyanopyrazolo[1,5- a]pyridin-6-yl)oxy)methyl)morpholine- 4-carboxylate 701.2 (M + H) P151

tert-butyl (2-((4- (5-(4-(2-chloro-6- methylbenzamido)- 4-methylpiperidin-1- yl)pyrazin-2-yl)-3- cyanopyrazolo[1,5- a]pyridin-6-yl)oxy)ethyl)carbamate 645.2 (M + H)

Intermediate P152

N-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-2-chloro-6-methylbenzamidebis(2,2,2-trifluoroacetate)

A solution tert-butyl(2-((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate(Intermediate P151; 134 mg, 0.208 mmol) in DCM (1 mL) and TFA (0.5 mL,6.53 mmol) was stirred overnight at ambient temperature. The reactionmixture was concentrated in vacuo to afford the title compound (161 mg,quantitative yield). MS (apci) m/z=545.2 (M+H).

Intermediate P153

Tert-butyl3-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate

In a pressure tube, a mixture of tert-butyl3-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(Intermediate P144; 155 mg, 0.328 mmol),1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-aminebis(2,2,2-trifluoroacetate) (Intermediate R47; 149 mg, 0.328 mmol), wastreated with 2 M K₃PO_(4(aq)) (492 μL, 0.984 mmol), X-phos (31.3 mg,0.0656 mmol) and Pd₂(dba)₃ (15.0 mg, 0.0164 mmol) in dioxane (1.64 mL)was sparged with Ar_((g)) for 3 min, and then the vessel was sealed. Thereaction mixture was stirred for 4 h at 80° C. After cooling to ambienttemperature, the reaction mixture was purified directly, first by silicachromatography (using 0-30% MeOH in DCM as the gradient eluent) then byC18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFAas the gradient eluent) to afford the TFA salt of the title compound.The TFA salt was diluted with DCM, then extracted with saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to cleanly afford thetitle compound (27 mg, 15% yield). MS (apci) m/z=473.2 (M+H).

Intermediate P154

Tert-butyl3-(((4-(5-(4-(2-chloro-5-fluorobenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate

A solution of 2-chloro-5-fluorobenzoic acid (5.9 mg, 0.034 mmol),tert-butyl3-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(Intermediate P153; 6 mg, 0.011 mmol), DIEA (20 μL, 0.11 mmol) and HATU(8.5 mg, 0.022 mmol) in DCM (112 μL) was stirred overnight at ambienttemperature. The resulting mixture was purified directly by silicachromatography (using 0-100% EtOAc in Hexanes as the gradient eluent) tocleanly provide the title compound (3 mg, 39% yield). MS (apci)m/z=693.2 (M+H).

Intermediate P155

(S)-4-(6-(4-amino-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate(Intermediate P99; 133.0 mg, 0.2259 mmol) in dioxane (5.0 mL) wastreated with 12 M HCl(aq) (37.1 μL, 0.452 mmol). The resulting mixturewas stirred for 4 d at ambient temperature before concentrating themixture in vacuo. The residue was dissolved in 4:1 DCM:iPrOH, andextracted with saturated NaHCO_(3(aq)) (2×). The aqueous extracts werewashed with additional 4:1 DCM:iPrOH (3×). The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated invacuo to cleanly afford the title compound (70.1 mg, 64% yield). MS(apci) m/z=489.3 (M+H).

Intermediate P156

Intermediate P156 was isolated as a side product in the preparation ofethyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-4-carboxylate(Example 701).

Intermediate P157

2-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamidebis(2,2,2-trifluoroacetate)

A solution tert-butyl3-(((4-(5-(4-(2-chloro-5-fluorobenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[15-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(Intermediate P154; 19 mg, 0.027 mmol) in DCM (2 mL) and TFA (2 mL, 13mmol) was stirred for 2 h at ambient temperature. The reaction mixturewas concentrated in vacuo to afford the title compound (16 mg, 73%yield). MS (apci) m/z=593.2 (M+H).

Intermediate P158

tert-butyl((3r,4r)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)carbamate

A mixture of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.204 g, 0.723 mmol), tert-butyl((3r,4r)-4-hydroxypiperidin-3-yl)carbamate (0.313 g, 1.45 mmol) and DIEA(0.378 ml, 2.17 mmol) in DMSO (1.81 mL) was heated at 90° C. overnight.After cooling to RT, the reaction mixture was partitioned between EtOAcand water. After phase-separation, the aqueous layer was extracted withEtOAc. The organic extracts were combined, washed with brine, dried withNa₂SO₄ and concentrated to yield the title product (0.33 g, 0.69 mmol,95% yield). MS (apci) m/z=479.2 (M+H).

Intermediate P159

4-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3R,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate.A mixture of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P93, 0.206 g, 0.768 mmol), tert-butyl((3R,4S)-3-hydroxypiperidin-4-yl)carbamate (0.216 g, 0.998 mmol) andDIEA (0.669 mL, 3.84 mmol) in DMSO (1.92 mL) was heated to 90° C.overnight. The reaction mixture was worked up with EtOAc and water. Theorganic layers were washed with brine, dried with Na₂SO₄, filtered andconcentrated. The crude material was purified by silica chromatography(1-10% MeOH in DCM) to yield the title product (0.223 g, 62.5% yield).MS (apci) m/z=465.2 (M+H).

Step 2: Preparation of4-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Tert-butyl((3R,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(0.223 g, 0.480 mmol) was taken up in DCM and TFA (1 mL each) andstirred for 1 h. The mixture was concentrated, taken up in DCM andstirred with MP-carbonate for 20 min. The mixture was filtered andconcentrated to give the title product (0.055 g, 31.4% yield). MS (apci)m/z=365.1 (M+H).

Intermediate P160

tert-butyl((3S,4S)-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate

A solution of3-chloro-6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 425, Step 2; 93.1 mg, 0.319 mmol) and tert-butyl((3S,4S)-3-hydroxypiperidin-4-yl)carbamate (104 mg, 0.479 mmol) in DMSO(2 mL) was treated with DIEA (0.279 mL, 1.60 mmol) and stirred at 1150Covernight. After cooling to RT, the reaction mixture was diluted withwater and filtered, yielding the title compound (112 mg, 72% yield). MS(apci) m/z=488.2 (M+H).

Intermediate P161

(3S,4S)-4-amino-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-olDihydrochloride

A solution of tert-butyl((3S,4S)-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Intermediate P160, 110 mg, 0.225 mmol) in 1,4-dioxane (2 mL, 0.225mmol) was treated with HCl (0.0370 mL, 0.451 mmol) and stirred at RTovernight. Removal of solvent under vacuum yielded the title compound assolid assuming quantitative yield. MS (apci) m/z=388.2 (M+H).

Intermediate P162

tert-butyl((3S,4S)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate

Step 1: Preparation of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)carbamate.A mixture of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.270 g, 0.957 mmol), tert-butyl((3S,4R)-4-hydroxypiperidin-3-yl)carbamate (0.414 g, 1.91 mmol) andHunig's base (0.500 ml, 2.87 mmol) in DMSO (2.39 mL) was heated to 90°C. overnight. The reaction mixture was worked up with EtOAc and water.The organic layers were washed with brine, dried with Na₂SO₄, filteredand concentrated to yield the title compound (0.291 g, 63.6% yield). MS(apci) m/z=479.2 (M+H).

Step 2: Preparation of(3S,4R)-3-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-ylmethanesulfonate. A mixture of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)carbamate(0.291 g, 0.608 mmol), methanesulfonyl chloride (0.0471 ml, 0.608 mmol)and Hunig's base (0.159 ml, 0.912 mmol) in DCM (6.08 mL) was stirred atRT overnight. The mixture was the worked up with DCM and water. Theorganic layers were washed with brine, dried with Na₂SO₄, filtered andconcentrated to yield the title compound (0.293 g, 86.6% yield). MS(apci) m/z=557.2 (M+H).

Step 3: Preparation of tert-butyl((3S,4S)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate.(3S,4R)-3-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-ylmethanesulfonate (0.293 g, 0.526 mmol) and NaN₃ (0.0513 g, 0.790 mmol)in DMF (2.11 mL) was heated to 90° C. overnight. The mixture was workedup with DCM and water. The organic layers were washed with brine, driedwith Na₂SO₄, filtered and concentrated. The crude material was purifiedby silica chromatography (1-10% MeOH in DCM) to yield the title compound(0.177 g, 66.8% yield). MS (apci) m/z=504.2 (M+H).

Step 4: Preparation of tert-butyl((3S,4S)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate.Tert-butyl((3S,4S)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(0.177 g, 0.351 mmol) and Pd/C (0.00748 g, 0.0703 mmol) in MeOH (3.51mL) was stirred under H₂ balloon overnight. This was the filtered andconcentrated to give the title compound (0.152 g, 90.6% yield). MS(apci) m/z=478.2 (M+H).

Intermediate P163

4-(5-(4-amino-4-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(5-bromopyrimidin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)boronic acid(Intermediate P127, 86 mg, 0.27 mmol) and 5-bromo-2-iodopyrimidine (78mg, 0.27 mmol) in dioxane (2 mL) and water (0.8 mL) was added XPhos (26mg, 0.054 mmol), Pd₂(dba)₃ (12 mg, 0.014 mmol) and 2M K₃PO₄ (0.4 mL, 0.8mmol). The reaction was heated to 60° C. for 3 hours. After cooling toRT, the reaction was partitioned between DCM and water (15 mL each),followed by extracting the aqueous with DCM (2×15 mL). The organicextracts were combined and concentrated. The crude material was purifiedby silica chromatography (0 to 100% acetone in hexanes) to yield thetitle compound (48 mg, 41%). MS (apci) m/z=429.1, 431.1 (M+H).

Step 2: Preparation of tert-butyl(1-(2-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate.A mixture of4-(5-bromopyrimidin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(48 mg, 0.11 mmol), tert-butyl (4-methylpiperidin-4-yl)carbamate (36 mg,0.17 mmol), Cs₂CO₃ (73 mg, 0.22 mmol), XPHOS (11 mg, 0.022 mmol) andPd₂dba₃ (10 mg, 0.011 mmol) in dioxane (1 mL) was heated at 90° C.overnight. The reaction mixture was diluted with water (25 mL) andextracted with DCM (2×25 mL). The combined organic extracts werefiltered through a Celite® pad and concentrated under reduced pressure.The crude material was purified by silica chromatography (10-100%acetone in hexanes) to yield the title compound (22 mg, 35%). MS (apci)m/z=563.3 (M+H).

Step 3: Preparation of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.A mixture of tert-butyl(1-(2-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate(22 mg, 0.04 mmol) in 1:1 DCM:TFA was stirred at RT for 1 h and thenconcentrated. The crude material was taken up in minimal amount of MeOHand passed thru a P1-HCO₃ resin plug. Removal of solvent under reducedpressure yielded the title compound with quantitative yield. MS (apci)m/z=463.2 (M+H).

Intermediate P164

(S)-4-bromo-6-(2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1; 500 mg, 2.10 mmol) in DMF (4 mL) was treatedsequentially with K₂CO_(3(s)) (1451 mg, 10.5 mmol) and(S)-2-methyloxirane (1830 mg, 31.5 mmol). The reaction mixture wasstirred for 3 d at 50° C. in a sealed vessel. After cooling to ambienttemperature, the reaction mixture was diluted with water (50 mL) andextracted with DCM (2×50 mL). The combined organic extracts were washedwith brine (50 mL). The resultant emulsion was filtered through a coarseglass frit, and the biphasic filtrate was separated. The organicextracts were washed again with brine (50 mL), then dried over anhydrousMgSO_(4(s)), filtered and concentrated in vacuo. The crude residue waspurified by silica chromatography (using 0-90% EtOAc/Hexanes as thegradient eluent) to cleanly provide the title compound (357 mg, 57%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 8.14 (d, 1H), 7.49 (d,1H), 4.25 (m, 1H), 3.96 (dd, 1H), 3.86 (dd, 1H), 1.33 (d, 3H).

Intermediate P165

(S)-4-(6-fluoropyridin-3-yl)-6-(2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube, a solution of(S)-4-bromo-6-(2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P164; 357 mg, 1.21 mmol) in dioxane (6 mL) was treatedwith 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(323 mg, 1.45 mmol), and 2 M Na₂CO_(3(aq)) (1808 μL, 3.62 mmol) wassparged with N_(2(g)) for 5 min. The resulting mixture was treated withPd(PPh₃)₄ (34.8 mg, 0.0301 mmol) then sparged again with N_(2(g)) for 5min, before sealing the vessel. The reaction mixture was stirred for 22h at 80° C. After cooling to ambient temperature, the reaction mixturewas diluted with water (25 mL) and stirred for 1 h. The resultingsuspension was vacuum filtered and the solids were collected to cleanlyprovide the title compound (191 mg, 51% yield). MS (apci) m/z=313.1(M+H).

Intermediate P166

6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure vessel, a mixture of4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P41; 2.0 g, 6.4 mmol), bis(pinacolato)diboron (2.5 g, 9.7mmol), PdCl₂(dppf).CH₂Cl₂ (0.53 g, 0.64 mmol), and KOAc (1.9 g, 19 mmol)in dioxane (15 mL) was sparged with Ar_((g)) for 10 min. The vessel wassealed and the mixture was stirred overnight at 90° C. After cooling toroom temperature, the reaction mixture was diluted with EtOAc (100 mL).The resulting suspension was filtered, and the filter cake was washedwith EtOAc. The filtrate was concentrated in vacuo, and the residue waspurified by silica chromatography (25% EtOAc in Hexanes as the eluent)to afford the title compound (2.2 g, 91% yield). ¹H-NMR (400 MHz, CDCl₃)δ: 8.19 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H), 3.80(s, 2H), 1.41 (s, 12H), 1.35 (s, 6H).

Intermediate P167

3-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

A mixture of 4-bromo-3-chloro-6-methoxypyrazolo[1,5-a]pyridine(Intermediate P84, Step 1; 152 mg, 0.581 mmol), PdCl₂(dppf).CH₂Cl₂ (23.7mg, 0.029 mmol), KOAc (285 mg, 2.91 mmol) and bis(pinacolato)diboron(443 mg, 1.74 mmol) in dioxane (5.8 mL) was sparged with Ar_((g)). Thereaction vessel was sealed, and the mixture was stirred for 2 h 15 minat 90° C. After cooling to ambient temperature, the reaction mixture wasfiltered through Celite®. The filtrate was concentrated in vacuo toafford the title compound (102 mg, 57%). MS (apci) m/z=309.1 (M+H).

Intermediate P168

6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1, Step 6; 150 mg, 0.6 mmol), PdCl₂(dppf) (17 mg, 0.02mmol), KOAc (165 mg, 1.7 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (267 mg,1.05 mmol) in dioxane (4 mL) was sparged with argon, then heated to 90°C. for 3 h. After cooling to RT, the reaction was filtered throughCelite® and concentrated. The crude material was purified by silicachromatography (0-10% MeOH/DCM) to afford the title product (126 mg,70%).

Intermediate P169

4-bromo-6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbutoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1; 194 mg, 0.815 mmol) in DMA (4.0 mL, 0.815 mmol) wasadded K₂CO₃ (338 mg, 2.44 mmol) then((4-bromo-2-methylbutan-2-yl)oxy)(tert-butyl)dimethylsilane (459 mg,1.63 mmol). The reaction was sealed and heated at 60° C. overnight.After cooling to RT, the reaction was diluted with brine and filtered,rinsed with water. The solid obtained was dissolved in minimal amount ofDCM, followed by addition of Et₂O to induce precipitation. After stirredfor 2 h, the suspension was filtered to afford the title product (250mg, 70%). 1H-NMR (400 MHz, CDCl₃) δ: 8.19 (s, 1H), 8.09 (br d, 1H), 7.42(br d, 1H), 4.13 (t, 2H), 1.97 (t, 2H), 1.31 (s, 6H), 0.86 (s, 9H), 0.10(s, 6H).

Intermediate P170

4-bromo-6-(2-(3,3-difluoroazetidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-bromo-6-(2-chloroethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P125; 50 mg, 0.17 mmol) in DMF (0.33 mL) were added DIEA(291 μl, 1.7 mmol), followed by 3,3-difluoroazetidine (46 mg, 0.50mmol). The reaction was stirred at 60° C. for 4 d, after whichadditional 3,3-difluoroazetidine (46 mg, 0.50 mmol) was added andheating resumed for another 16 h to reach completion. The reaction wasdiluted with water and filtered to afford the title product, which wasdirectly used without further purifications (31 mg, 37%). MS (apci)m/z=357, 359 (M+H).

Intermediate P171

4-bromo-6-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1; 100 mg, 0.420 mmol) in DMA (2 mL) were added K₂CO₃(87.1 mg, 0.63 mmol) then 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (74.4mg, 0.504 mmol). The reaction was heated at 50° C. overnight, thenpoured into water (10 mL) and stirred for 1 h before it was filtered andrinsed with water (5 mL), yielding the title product as beige solid (127mg, 86%). ¹H NMR (CDCl₃) δ 8.20 (s, 1H), 8.19 (d, 1H), 7.50 (d, 1H),4.66 (s, 2H), 3.54 (t, 2H), 3.47 (t, 2H), 2.04 (m, 2H), 1.90 (m, 2H).

Intermediate P172

4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate

A mixture of6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P110; 500 mg, 1.60 mmol), tert-butyl(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (IntermediateR46; 521.8 mg, 1.60 mmol), K₃PO₄ (2 M aq, 2.4 mL, 4.79 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (152.2mg, 0.32 mmol) and Pd₂(dba)₃ (73.10 mg, 0.080 mmol) in 1,4-dioxane (8.0mL) was degassed with argon for 3 min, then sealed and heated to 80° C.overnight. After an aqueous workup the crude material was purified usingsilica chromatography (0-100% EtOAc in hexanes) to afford the titleproduct (338.5 mg, 44%). MS (apci) m/z=478.2 (M+H).

Step 2: Preparation of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate). To a solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate(338.5 mg, 0.71 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid(2 mL). After stirred at RT for 1 h, the reaction was diluted with Et₂O(20 mL) and filtered to afford the title product (342 mg, 80%). MS(apci) m/z=378.1 (M+H).

Intermediate P173

4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

The title product was prepared according to the procedure described inIntermediate P172, replacing6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilewith6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P166) in Step 1. MS (apci) m/z=422.3 (M+H).

Intermediate P174

4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) Step 1: Preparation of tert-butyl(4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperidin-4-yl)carbamate

In a pressure vessel were combined tert-butyl(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (IntermediateR46; 26 mg, 0.080 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (202 mg,0.80 mmol), PdCl₂(dppf)-DCM (6.5 mg, 0.0080 mmol), KOAc (39 mg, 0.40mmol) and dioxane (796 μl). The reaction mixture was sparged with argonfor 10 min before it was sealed and heated to 90° C. overnight. Aftercooling to RT, the reaction was partitioned between DCM and water,extracting the aqueous with DCM (3×) after phase-separation. Thecombined organic extracts were washed with brine, then dried (Na₂SO₄),filtered and concentrated. The crude material was used directly in thenext step assuming quantitative yield.

Step 2: Preparation of tert-butyl(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate

A mixture of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P1, Step 6; 300 mg, 1.19 mmol), tert-butyl(4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperidin-4-yl)carbamate(1158 mg, 1.19 mmol), Pd(Ph₃P)₄ (138 mg, 0.119 mmol) and Na₂CO₃ (2 M aq,3.6 mL, 7.14 mmol) in dioxane (6.0 mL) was sparged with argon for 10 minthen heated to 80° C. overnight. After cooling to ambient temperature,the reaction was diluted with water (10 mL) and extracted with 4:1DCM:IPA (5×10 mL). The combined organic extractions was passed through aPhase Separator frit, and the filtrate was concentrated then purified bysilica gel chromatography (0-10% MeOH in DCM) to afford the titleproduct as solid (173 mg, 31%). MS (apci) m/z=464.2 (M+H).

Step 3: Preparation of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate). To a solution of tert-butyl(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate(173 mg, 0.336 mmol) in DCM (2 mL) was added TFA (2 mL). After stirredat RT for 30 min, the reaction was diluted with Et₂O (20 mL) andfiltered to yield the title product (163 mg, 78%). MS (apci) m/z=364.2(M+H).

Intermediate P175

1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-amine

A mixture of3-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(P167 55 mg, 0.18 mmol),1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-amine (R47, 40 mg, 0.18mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane(17 mg, 0.036 mmol)), and Pd₂(dba)₃ (8.2 mg, 0.0089 mmol) in 1,4-dioxane(891 μL) and K₃PO₄ (2 M aq, 267 μL) was sparged with argon before sealedand heated to 80° C. overnight. After cooling to RT, the reaction wasdiluted with DCM, washed with water and brine, then dried (Na₂SO₄),filtered and concentrated. The residue was purified using silicachromatography (0-20% MeOH in DCM with 0.2% NH₄OH) to afford the titlecompound (29 mg, 44%). LCMS m/z=373.1 (M+H).

Intermediate P176

tert-butyl(R)-2-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate

The title compound (36 mg, 16%) was prepared by a similar method asdescribed in Intermediate P175, replacing3-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridinewith tert-butyl(R)-2-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P140). LCMS m/z=549.3 (M+H).

Intermediate P177

tert-butyl(S)-2-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate

The title compound (36 mg, 16%) was prepared by a similar method asdescribed in Intermediate P175, replacing3-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridinewith tert-butyl(S)-2-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P146). LCMS m/z=549.3 (M+H).

Intermediate R3

4-Ethyl-N-isopropyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-4-carboxamideStep 1: Preparation of1-(5-boronopyridin-2-yl)-4-ethylpiperidine-4-carboxylic Acid

A solution of2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 g,9.0 mmol) in DMSO (18 mL) was treated with4-ethylpiperidine-4-carboxylic acid (4.7 g, 30 mmol) and K₂CO_(3(s))(5.0 g, 36 mmol). The resulting mixture was stirred overnight at 80° C.After cooling to ambient temperature, the reaction mixture was dilutedwith water, and extracted with 20% MeOH/DCM. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (4.2 g, quantitativeyield). The material was carried forward without further purification.MS (apci) m/z=320.2 (M+H).

Step 2: Preparation of4-Ethyl-N-isopropyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-4-carboxamide

A solution of 1-(5-boronopyridin-2-yl)-4-ethylpiperidine-4-carboxylicacid (2.45 g, 8.81 mmol) in DMA (35 mL) was treated sequentially withDIEA (8.44 mL, 48.5 mmol), propan-2-amine (2.25 mL, 26.4 mmol), and HATU(8.37 g, 22.0 mmol), then stirred overnight at ambient temperature. Theresulting mixture was diluted with water, and extracted with 20%MeOH/DCM. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo. The crude residue waspurified by C18 reverse phase chromatography (0-80% ACN/water as thegradient eluent) to cleanly provide the title compound (1.0 g, 36%yield). MS (apci) m/z=411.2 (M+H).

Intermediate R8

N-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.1]heptan-6-amine (TFA salt)Step 1: Preparation of tert-butyl6-((6-methoxypyridin-3-yl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate

Under an atmosphere of N_(2(g)), a solution of tert-butyl6-oxo-3-azabicyclo[3.1.1]heptane-3-carboxylate (40 mg, 0.19 mmol) and6-methoxypyridin-3-amine (33 mg, 0.27 mmol) in 1:1 MeOH: DCE (1.5 mL)was treated with decaborane (6.9 mg, 0.057 mmol). After stirringovernight at ambient temperature, the reaction mixture was quenched withwater. The resulting biphasic mixture was extracted with DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The crude residue was purified bysilica chromatography (40-100% EtOAc/Hexanes as the gradient eluent) toafford the title compound (56 mg, 93% yield). MS (apci) m/z=320.2 (M+H).

Step 2: Preparation ofN-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.1]heptan-6-amine (TFA Salt)

A solution of tert-butyl6-((6-methoxypyridin-3-yl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate(56 mg, 0.175 mmol) in DCM (500 μL) was treated with trifluroacetic acid(TFA) (0.40 mL, 5.26 mmol and stirred overnight at ambient temperature.The reaction mixture was concentrated in vacuo and purified by C18reverse phase chromatography (5-95% water-ACN with 0.01% TFA as thegradient eluent) to cleanly provide the title compound as TFA salt. (25mg, 65% yield). MS (apci) m/z=220.1 (M+H).

Intermediate R13

(2-methoxy-5-(piperidin-4-yloxy)pyridine Step 1: Preparation oftert-butyl 4-((6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate

A solution of 6-methoxypyridin-3-ol (100 mg, 0.799 mmol) and tert-butyl4-hydroxypiperidine-1-carboxylate (161 mg, 0.799 mmol) in THF wastreated with PPh₃ (231 mg, 0879 mmol), then sparged with Ar_((g)) for 5min. While stirring at ambient temperature, the mixture was treatedslowly with DIAD (186 μL, 0.959 mmol). The resulting reaction mixturewas stirred for 9 h at ambient temperature, then overnight at 70° C.before introducing additional DIAD (186 μL, 0.959 mmol). The reactionmixture was stirred for 4 h at 70° C. and then allowed to cool toambient temperature. After concentrating the reaction mixture in vacuo,the residue was suspended in DCM and washed with saturatedNa₂CO_(3(aq)), water and brine. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (246 mg, quantitative yield). MS (apci)m/z=309.15 (M+H).

Step 2: Preparation of 2-methoxy-5-(piperidin-4-yloxy)pyridine

A solution of tert-butyl4-((6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate (246 mg, 0.80mmol) in DCM (4.0 mL) was treated with TFA (4.0 mL, 0.80 mmol), thenstirred for 5 min at ambient temperature before introducing additionalTFA (1 mL). After stirring for 45 min at ambient temperature, thereaction mixture was concentrated in vacuo. The crude residue waspurified by silica chromatography (1-9% MeOH in DCM with 0.1-0.9% NH₄OHas the gradient eluent) to cleanly provide the title compound (127.5 mg,77% yield). MS (apci) m/z=209.1 (M+H).

Intermediate R14

Tert-butyl (R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

A solution of N-tert-Butoxycarbonyl-(R)-(−)-3-pyrrolidinol (2.0 g, 10.7mmol) in DCM (28 mL) was treated with TEA (2.9 mL, 21.4 mmol). Thesolution was cooled to 0° C. for 30 minutes. Then methanesulfonylchloride (868 μL, 11.2 mmol) was added. The reaction was stirred at 0°C. for 30 minutes. The reaction was diluted with DCM and washed withsaturated NaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (5-95% EtOAc in Hexanes as thegradient eluent) to afford the title compound (2.83 g, 100% yield). ¹HNMR (400 MHz, DMSO-d6) δ 5.24 (s, 1H), 3.55-3.38 (m, 3H), 3.31-3.27 (m,1H), 3.23 (s, 3H), 2.18-2.08 (m, 2H), 1.40 (s, 9H).

Intermediate R15

4-ethyl-N-phenylpiperidine-4-carboxamide Step 1: Preparation oftert-butyl 4-ethyl-4-(phenylcarbamoyl)piperidine-1-carboxylate

A solution of 1-(tert-butoxycarbonyl)-4-ethylpiperidine-4-carboxylicacid (269.5 mg, 1.047 mmol) and HATU (477.9 mg, 1.257 mmol) in DMF (3.9mL) was treated with DIEA (3.649 mL, 2.095 mmol) and aniline (0.1051 mL,1.152 mmol). The reaction mixture was stirred at 60° C. for 60 h. Thereaction mixture was diluted with EtOAc and washed successively withwater and saturated NaCl_((aq)). The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 348.1 mg, 1.047 mmol) in sufficient purity for step 2. MS (apci)m/z=233.2 (M+H−Boc).

Step 2: Preparation of 4-ethyl-N-phenylpiperidine-4-carboxamide

A solution tert-butyl4-ethyl-4-(phenylcarbamoyl)piperidine-1-carboxylate (348.1 mg, 1.047mmol) in DCM (2 mL) was treated with TFA (2 mL) and stirred at rt for 1h. The reaction mixture was concentrated in vacuo. The residue wasdiluted with saturated NaHCO_(3(aq)) and extracted with 4:1 DCM/IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo to afford the title compound (162.4 mg, 0.6990mmol, 66.7% yield over two steps). MS (apci) m/z=233.1 (M+H).

Intermediate R16

4-ethyl-N-isobutylpiperidine-4-carboxamide Step 1: Preparation oftert-butyl 4-ethyl-4-(isobutylcarbamoyl)piperidine-1-carboxylate

A solution of 1-(tert-butoxycarbonyl)-4-ethylpiperidine-4-carboxylicacid (260.3 mg, 1.012 mmol) and HATU (461.5 mg, 1.214 mmol) in DMF (3.9mL) was treated with DIEA (3.524 mL, 2.023 mmol) and2-methylpropan-1-amine (81.38 mg, 1.113 mmol). The reaction mixture wasstirred at 60° C. for 60 h. The reaction mixture was diluted with EtOAcand washed successively with water and saturated NaCl_((aq)). Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(1-95% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 216 mg, 1.012 mmol) in sufficientpurity for step 2. MS (apci) m/z=213.2 (M+H−Boc).

Step 2: Preparation of 4-ethyl-N-isobutylpiperidine-4-carboxamide

A solution tert-butyl4-ethyl-4-(isobutylcarbamoyl)piperidine-1-carboxylate (216 mg, 1.012mmol) in DCM (1 mL) was treated with TFA (1 mL) and stirred at rt for 16h. The reaction mixture was concentrated in vacuo. The residue wasdiluted with saturated NaHCO_(3(aq)) and extracted with 4:1 DCM/IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo to afford the title compound (100.8 mg, 0.3988mmol, 39% yield over two steps). MS (apci) m/z=213.2 (M+H).

Intermediate R17

4-(benzylsulfonyl)piperidine Step 1: Preparation of tert-butyl4-(benzylthio)piperidine-1-carboxylate

A solution of tert-butyl 4-mercaptopiperidine-1-carboxylate (211.2 mg,0.9718 mmol) and benzyl bromide (199.5 mg, 1.166 mmol) in DMF (3.9 mL)was treated with potassium carbonate (537.2 mg, 3.887 mmol). Thereaction mixture was stirred at 70° C. for 60 h. After cooling toambient temperature, the reaction mixture was diluted with EtOAc andwashed successively with water and saturated NaCl_((aq)). The combinedorganic extracts were concentrated in vacuo, and the residue waspurified by silica chromatography (1-50% EtOAc in hexanes as thegradient eluent) to afford the title compound (290.1 mg, 0.9436 mmol,97% yield) in sufficient purity for step 2. MS (apci) m/z=208.1(M+H−Boc).

Step 2: Preparation of tert-butyl4-(benzylsulfonyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(benzylthio)piperidine-1-carboxylate(290.1 mg, 0.9436 mmol) in DCM (9.5 mL) was added 3-chlorobenzoperoxoicacid (488.5 mg, 2.831 mmol). The reaction mixture was stirred at 0° C.and gradually warmed to rt, then stirred at rt for 16 h. The reactionmixture was concentrated in vacuo, and the residue was purified bysilica chromatography (0-95% EtOAc in hexanes as the gradient eluent) toafford the title compound (assumed theoretical yield, 320.3 mg, 0.9436mmol) in sufficient purity for step 3. MS (apci) m/z=240.1 (M+H−Boc).

Step 3: Preparation of 4-(benzylsulfonyl)piperidine

A solution of tert-butyl 4-(benzylsulfonyl)piperidine-1-carboxylate(320.3 mg, 0.9436 mmol) in DCM (2 mL) was treated with TFA (2 mL, 26mmol). The reaction mixture was stirred at rt for 15 min. The reactionmixture was washed with saturated NaHCO_(3(aq)) then extracted with 4:1DCM/IPA. The combined organic extracts were concentrated in vacuo toafford the title compound (138.0 mg, 0.5766 mmol, 61.1% yield over twosteps). MS (apci) m/z=240.1 (M+H).

Intermediate R18

N-isopropylpiperidine-4-sulfonamide Step 1: Preparation of tert-butyl4-(N-isopropylsulfamoyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate(1.0137 g, 3.5723 mmol) in DCM (2 mL) was treated with pyridine (722 μL,8.93 mmol) and propan-2-amine (460 μL, 5.36 mmol), then stirredovernight at ambient temperature. The resulting mixture was washed withwater (4×). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound insufficient purity to carry into step 2 (1.09 g, quantitative yield). MS(apci) m/z=207.2 [(M−Boc)+H].

Step 2: Preparation of N-isopropylpiperidine-4-sulfonamide

Crude tert-butyl 4-(N-isopropylsulfamoyl)piperidine-1-carboxylate (1.09g, 3.56 mmol) was suspended in DCM (5 mL) and treated with TFA (2.5 mL,32 mmol). The resulting mixture was stirred for 3 h at ambienttemperature before concentrating the mixture in vacuo. The crude residuewas suspended in 4:1 DCM:iPrOH, and extracted with saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (734 mg, quantitative yield). MS (apci) m/z=207.2 (M+H).

Intermediate R19

Isopropyl (4-methylpiperidin-4-yl)carbamate Step 1: Preparation oftert-butyl4-((isopropoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate

A mixture of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (546.5mg, 2.550 mmol) and DIEA (1113 μL, 6.375 mmol) in DCM (164.1 μL) wascooled to 0° C., then treated dropwise (over 10 min) with isopropylcarbonochloridate (3825 μL, 3.825 mmol). After being allowed togradually warm to ambient temperature, the mixture was stirred overnightat ambient temperature. The mixture was concentrated in vacuo, and thecrude residue was purified by silica chromatography (using 0-100%Hexanes/EtOAc as the gradient eluent) to cleanly afford the titlecompound (746.6 mg, 97% yield). MS (apci) m/z=201.2 (M+H).

Step 2: Part A: Preparation of isopropyl(4-methylpiperidin-4-yl)carbamate

A mixture of tert-butyl4-((isopropoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (315.0mg, 1.049 mmol) in DCM (4 mL) was treated dropwise with TFA (2.5 mL, 32mmol). The resulting mixture was stirred for 1 h at ambient temperaturebefore concentrating the mixture in vacuo. The crude residue wassuspended in DCM, treated with saturated NaHCO_(3(aq)), and then thebiphasic mixture was extracted with 4:1 DCM:iPrOH. The aqueous phase wasset aside for Step 2: Part B. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (96.0 mg, 46% yield). MS (apci) m/z=201.2(M+H).

Step 2: Part B: Preparation of isopropyl(4-methylpiperidin-4-yl)carbamate Hydrochloride

Additional title compound, in the form of the HCl salt, was extractedfrom the aqueous phase by adjusting the pH of the aqueous extracts to pH2 with the addition of 2M HCl_((aq)). The acidified aqueous extractswere concentrated in vacuo, reducing the volume by half. Trituration ofthis mixture with dioxane afforded a precipitate, which was collected byfiltration. Subsequent, air drying of the solids provided the HCl saltof the title compound (182.7 mg, quantitative yield based on expectedrecovery). MS (apci) m/z=201.2 (M+H):

Intermediate R20

tert-butyl (3S,4S)-3-hydroxy-4-(3-methylbutanamido)pyrrolidine-1-carboxylate

A solution of tert-butyl(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (355.5 mg, 1.758mmol) in DCM (2 mL) was treated with DIEA (921.0 μL, 5.273 mmol) thenstirred for 30 min at 0° C. The 0° C. mixture was treated dropwise withisovaleryl chloride (235.7 μL, 1.933 mmol). The resulting mixture wasstirred for 20 min, over which time the temperature was allowed togradually reach ambient temperature. The reaction mixture was dilutedwith DCM, and washed with saturated NaHCO_(3(aq)). The organic extractswere directly purified by silica chromatography (using 20-100% EtOAc inHexanes as the gradient eluent) to cleanly provide the title compound(487.2 mg, 97% yield). MS (apci) m/z=187.2 ([M−boc]+H).

Intermediate R21

N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methylbutanamide hydrochloride

A solution of tert-butyl(3S,4S)-3-hydroxy-4-(3-methylbutanamido)pyrrolidine-1-carboxylate(Intermediate R20; 487.2 mg, 1.701 mmol) in dioxane (2.0 mL) was treatedwith 12 M HCl_((aq)) (139.7 μL, 1.701 mmol). The resulting mixture wasstirred for 2 h at ambient temperature before concentrating the mixturein vacuo to afford the title compound (378 mg, 100% yield). MS (apci)m/z=187.2 (M+H−Boc).

Intermediate R22

Ethyl piperidine-4-carboxylate Hydrochloride

A solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (321.9mg, 1.251 mmol) in DCM (2.0 mL) was treated with TFA (2.0 mL, 25.96mmol). The resulting mixture was stirred overnight at ambienttemperature before concentrating the mixture in vacuo. The crude residuewas suspended in dioxane, and treated with 12 M HCl_((aq)). Theresulting mixture was concentrated in vacuo to afford the title compound(240 mg, 99% yield).

Intermediate R23

tert-butyl 4-((isopropylcarbamoyl)oxy)-4-methylpiperidine-1-carboxylate

A solution of 2-isocyanatopropane (50.5 mg, 0.593 mmol) in DCM (2 mL)and 12 M HCl_((aq)) (2.44 μL, 0.0297 mmol) was stirred 5 min at ambienttemperature, then added to tert-butyl4-hydroxy-4-methylpiperidine-1-carboxylate (172.1 mg, 0.7994 mmol). Thereaction mixture was stirred overnight at ambient temperature beforeintroducing additional 2-isocyanatopropane (50.5 mg, 0.593 mmol) and 12M HCl_((aq)) (2.44 μL, 0.0297 mmol). The resulting mixture was stirredfor 3 h at ambient temperature before another equivalent of2-isocyanatopropane (50.5 mg, 0.593 mmol) was introduced. After stirringovernight at ambient temperature, the reaction mixture was concentratedin vacuo. The crude residue was purified directly by silicachromatography (using 0-100% Hexanes/EtOAc as the gradient eluent) tocleanly provide the title compound (180 mg, quantitative yield). MS(apci) m/z=201.2 (M+H).

Intermediate R24

4-methylpiperidin-4-yl isopropylcarbamate hydrochloride

A solution of to tert-butyl4-((isopropylcarbamoyl)oxy)-4-methylpiperidine-1-carboxylate(Intermediate R23; 60 mg, 0.20 mmol) in DCM (1.0 mL) was treated withTFA (1.0 mL, 13.0 mmol). The resulting mixture was stirred for 30 min atambient temperature before concentrating the mixture in vacuo. The cruderesidue was suspended in dioxane (1 mL), and treated with two drops ofconc. HCl_((aq)). The resulting mixture was concentrated in vacuo toafford the title compound (50 mg, quantitative yield). MS (apci)m/z=201.2 (M+H).

Intermediate R25

Cyclobutyl Carbonochloridate

The title compound (93.3 mg, 0.693 mmol, quantitative yield is assumed)was prepared and worked up using a similar procedure to that describedfor (S)-tetrahydrofuran-3-yl carbonochloridate (Intermediate R54),replacing (S)-tetrahydrofuran-3-ol (100 mg, 1.13 mmol) with cyclobutanol(54.3 μl, 0.693 mmol).

Intermediate R26

1-methoxycyclopropane-1-carboxylic Acid Step 1: Preparation of methyl1-methoxycyclopropane-1-carboxylate

A solution of 1-hydroxy-1-cyclopropanecarboxylic acid (1.02 g, 9.99mmol) in DMF (33 mL) was treated sequentially with iodomethane (1.56 mL,25.0 mmol) and NaH (60 wt. % in mineral oil; 1.00 g, 25.0 mmol), thenstirred for 16 h at ambient temperature. The resulting mixture wasdiluted with water, and then extracted with Et₂O (2×). The combinedorganic extracts were washed sequentially with water (3×) and brine(1×), and then dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound in sufficient purityto carry into step 2 (1.30 g, quantitative yield).

Step 2: Preparation of 1-methoxycyclopropane-1-carboxylic Acid

A solution of crude methyl 1-methoxycyclopropane-1-carboxylate (Step 1;1.30, 9.99 mmol, assumed) in 1:1 THF:MeOH (60 mL) was treated with 2.0 MKOH_((aq)). (14.99 mL, 29.97 mmol), then stirred for 60 h at ambienttemperature. The resulting mixture was diluted with Et₂O, and extractedwith 1.0 M NaOH(aq) (2×). The combined aqueous extracts were acidifiedto pH˜2 with the addition of 4.0 M HCl_((aq)), then extracted with DCM(2×). The combined DCM extracts were dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (240mg, 99% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 3.29 (s, 3H),1.14-1.04 (m, 4H).

Intermediate R27

tert-butyl (S)-3,4-dimethylpiperazine-1-carboxylate

A solution of tert-butyl (S)-3-methylpiperazine-1-carboxylate (4.9980 g,24.955 mmol) in DCM (10 mL) was treated with formaldehyde (37 wt % inwater with 5-15% MeOH stabilizer; 2.79 mL, 37.4 mmol), and stirred for2.5 h at ambient temperature. The reaction mixture was treated withNaBH(AcO)₃ (7.9334 mg, 37.432 mmol), and stirred overnight at roomtemperature. The reaction mixture was concentrated in vacuo. The residuewas diluted with 4:1 DCM:iPrOH, and filtered. The filtrate was extractedsequentially with saturated NaHCO_(3(aq)) (2×) and water. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to cleanly afford the title compound (3.9335 g,74% yield). MS (apci) m/z=215.2 (M+H).

Intermediate R28

(S)-1,2-dimethylpiperazine

A solution of tert-butyl (S)-3,4-dimethylpiperazine-1-carboxylate(Intermediate R27; 3.9335 g, 18.354 mmol) in DCM (2.0 mL) was treatedwith TFA (1.5 mL, 19.5 mmol). The resulting mixture was stirredovernight at ambient temperature before concentrating the mixture invacuo. The residue was diluted with 4:1 DCM:iPrOH, and extracted withsaturated NaHCO_(3(aq)). The aqueous extracts were back extracted with4:1 DCM:iPrOH. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to cleanly afford thetitle compound (2.0 g, 95% yield). MS (apci) m/z=115.3 (M+H).

Intermediate R29

N,N-dimethyl-4-(pyridin-2-ylmethyl)piperidin-4-aminebis(2,2,2-trifluoroacetate) Step 1: Preparation of tert-butyl4-(dimethylamino)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

A solution of tert-Butyl4-amino-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (50.2 mg, 0.172mmol) in DCM (1.15 mL) was treated with formaldehyde (37 wt. % in waterwith 5-15% MeOH stabilizer; 64.7 μl, 0.861 mmol) and NaBH(AcO)₃ (365 mg,1.72 mmol), and stirred for 1 h at ambient temperature. The reactionmixture was diluted with water and the biphasic mixture was extractedwith DCM (3×). The combined organic extracts were washed with brine.After back extracting all aqueous extracts once again with DCM, all DCMextracts were combined and concentrated in vacuo. The crude residue waspurified by silica chromatography (50-100% EtOAc/Hexanes followed by0-10% MeOH in EtOAc) to cleanly afford the title compound (55 mg, 100%yield). MS (apci) m/z=320.2 (M+H).

Step 2: Preparation ofN,N-dimethyl-4-(pyridin-2-ylmethyl)piperidin-4-aminebis(2,2,2-trifluoroacetate)

A mixture of tert-butyl4-(dimethylamino)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (55 mg,0.172 mmol) in DCM (2 mL) was treated with TFA (1 mL, 6.51 mmol). Theresulting mixture was stirred overnight at ambient temperature beforeconcentrating the mixture in vacuo to afford the title compound (77.0mg, quantitative yield). MS (apci) m/z=220.1 (M+H).

Intermediate R30

2-(dimethylamino)-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)acetamidebis(2,2,2-trifluoroacetate) Step 1: Preparation of tert-butyl4-(2-(dimethylamino)acetamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

A solution of 1 tert-butyl4-amino-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (50 mg, 0.172mmol) in DCM (1144 μL) was treated sequentially with HATU (78.3 mg,0.206 mmol), DIEA (59.8 μL, 0.343 mmol) and N,N-dimethylglycine (19.5mg, 0.189 mmol). The resulting mixture was stirred overnight at ambienttemperature, and then purified directly by C18 reverse phasechromatography (using 5-95% ACN/water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wassuspended in MeOH (5 mL), eluted through a basic resin (StratospheresP1-HCO3) to cleanly afford the title compound (50 mg, 77% yield). MS(apci) m/z=377.2 (M+H).

Step 2: Preparation of2-(dimethylamino)-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)acetamidebis(2,2,2-trifluoroacetate)

A mixture of tert-butyl4-(2-(dimethylamino)acetamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate(50 mg, 0.13 mmol) in DCM (1 mL) was treated with TFA (1 mL, 13.07mmol). The resulting mixture was stirred for 1 h at ambient temperatureto afford the title compound (50 mg, 75% yield). MS (apci) m/z=277.2(M+H).

The compounds in Table aaa were prepared using a similar 2 stepprocedure to that used for the synthesis of2-(dimethylamino)-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)acetamidebis(2,2,2-trifluoroacetate) (Intermediate R30) replacingN,N-dimethylglycine in step 1 with (1.0-1.1 equivalents) of theappropriate carboxylic acid.

TABLE aaa MS (apci) Int # Structure Chemical Name m/z R31

2-(piperidin-1-yl)-N-(4- (pyridin-2- ylmethyl)piperidin-4- yl)acetamidebis(2,2,2- trifluoroacetate) 317.3 (M + H) R32

1-methyl-N-(4-(pyridin-2- ylmethyl)piperidin-4-yl)- 1H-imidazole-5-carboxamide bis(2,2,2- trifluoroacetate) 300.2 (M + H) R33

2-(1-methyl-1H-imidazol- 2-yl)-N-(4-(pyridin-2- ylmethyl)piperidin-4-yl)acetamide bis(2,2,2- trifluoroacetate) 314.3 (M + H) R34

2-morpholino-N-(4- (pyridin-2- ylmethyl)piperidin-4- yl)acetamidebis(2,2,2- trifluoroacetate) 319.2 (M + H) R35

3-morpholino-N-(4- (pyridin-2- ylmethyl)piperidin-4- yl)propanamidebis(2,2,2- trifluoroacetate) 333.2 (M + H) R36

(9H-fluoren-9-yl)methyl (R)-(3-methyl-1-oxo-1- ((4-(pyridin-2-ylmethyl)piperidin-4- yl)amino)butan-2- yl)carbamate bis(2,2,2-trifluoroacetate) 513.2 (M + H) R37

(9H-fluoren-9-yl)methyl (S)-(3-methyl-1-oxo-1- ((4-(pyridin-2-ylmethyl)piperidin-4- yl)amino)butan-2- yl)carbamate bis(2,2,2-trifluoroacetate) 513.2 (M + H)

Intermediate R38

(R)-1-methyl-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)pyrrolidine-2-carboxamidebis(2,2,2-trifluoroacetate) Step 1: Preparation of tert-butyl(R)-4-(1-methylpyrrolidine-2-carboxamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

A solution of 1 tert-butyl4-amino-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (50 mg, 0.172mmol) in DCM (1144 μL) was treated sequentially with HATU (78.3 mg,0.206 mmol), DIEA (59.8 μL, 0.343 mmol) and N-methyl-D-prolinehydrochloride (28.4 mg, 0.172 mmol). The resulting mixture was stirredovernight at ambient temperature, and then purified directly by C18reverse phase chromatography (using 5-95% ACN/water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in MeOH (5 mL), eluted through a basic resin(Stratospheres P1-HCO3) to cleanly afford the title compound (55 mg, 80%yield). MS (apci) m/z=408.3 (M+H).

Step 2: Preparation of(R)-1-methyl-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)pyrrolidine-2-carboxamidebis(2,2,2-trifluoroacetate)

A mixture of tert-butyl(R)-4-(1-methylpyrrolidine-2-carboxamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate(55 mg, 0.14 mmol) in DCM (1 mL) was treated with TFA (1 mL, 13.07mmol). The resulting mixture was stirred for 1 h at ambient temperaturebefore concentrating the mixture in vacuo to afford the title compound(55 mg, 76% yield). MS (apci) m/z=303.2 (M+H).

Intermediate R39

(9H-fluoren-9-yl)methyl(R)-(1-oxo-1-((4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)propan-2-yl)carbamatebis(2,2,2-trifluoroacetate)

Step 1: Preparation of tert-butyl(R)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate.A solution of 1 tert-butyl4-amino-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (51.3 mg, 0.176mmol) in DCM (880 μL) was treated sequentially with HATU (80.3 mg, 0.211mmol), DIEA (61.3 μL, 0.352 mmol) and(((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine (58.0 mg, 0.176 mmol),then stirred at ambient temperature for 2 d. The reaction mixture waswashed with water, then dried over Na₂SO_(4(s)), filtered, andconcentrated. The crude was purified by silica chromatography (0-100%EtOAc/hexanes followed by 0-10% MeOH/EtOAc) to cleanly afford the titlecompound (107 mg, quantitative yield). MS (apci) m/z=585.2 (M+H).

Step 2: Preparation of (9H-fluoren-9-yl)methyl(R)-(1-oxo-1-((4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)propan-2-yl)carbamatebis(2,2,2-trifluoroacetate). A mixture of tert-butyl(R)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate(55 mg, 0.14 mmol) in DCM (1 mL) was treated with TFA (0.5 mL, 6.53mmol). The resulting mixture was stirred for 1 h at ambient temperaturebefore concentrating the mixture in vacuo to afford the title compound(130 mg, 100% yield). MS (apci) m/z=485.2 (M+H).

Intermediate R40

(R)-2-methoxy-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)propenamidebis(2,2,2-trifluoroacetate Step 1: Preparation of tert-butyl(R)-4-(2-methoxypropanamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

A solution of 1 tert-butyl4-amino-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (51.3 mg, 0.176mmol) in DCM (880 μL) was treated sequentially with HATU (80.3 mg, 0.211mmol), DIEA (61.3 μL, 0.352 mmol) and (R)-(+)-2-methoxypropionic acid(18.9 μL, 0.176 mmol). The resulting mixture was stirred overnight atambient temperature. The reaction mixture was purified directly bysilica chromatography (using a stepped gradient of 0-100% EtOAc/Hexfollowed by 0-10% MeOH/EtOAc) to cleanly afford the title compound(0.176 mmol, quantitative yield was assumed), which was carried directlyinto step 2. MS (apci) m/z=378.2 (M+H).

Step 2: Preparation of(R)-2-methoxy-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)propenamidebis(2,2,2-trifluoroacetate

A mixture of tert-butyl(R)-4-(2-methoxypropanamido)-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate(Step 1; 0.176 mmol) in DCM (1 mL) was treated with TFA (1 mL, 13.07mmol). The mixture was stirred for 1 h at ambient temperature beforeconcentrating the mixture in vacuo to afford the title compound (123 mg,quantitative yield). MS (apci) m/z=278.2 (M+H).

Intermediate R41

4-(pyridin-2-ylmethyl)piperidin-4-amine bis(2,2,2-trifluoroacetate)

A mixture of 1 tert-butyl4-amino-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (200 mg, 0.686mmol) in DCM (0.25 mL) was treated with TFA (0.25 mL, 3.27 mmol). Theresulting mixture was stirred for 1.75 h at ambient temperature beforeconcentrating the mixture in vacuo to afford the title compound (287 mg,100% yield). MS (apci) m/z=192.2 (M+H)

Intermediate R42

Ethyl 4-(hydroxymethyl)piperidine-4-carboxylate Hydrochloride Step 1:Preparation of 1-(tert-butyl) 4-ethyl4-(hydroxymethyl)piperidine-1,4-dicarboxylate

A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (6.86 g,26.6 mmol) in THF (30 mL) was cooled to −40° C. The cold solution wastreated slowly with LiHMDS (53.3 mL, 53.3 mmol) and stirred at −40° C.for 1 h. Subsequently, paraformaldehyde (3.20 g, 106.6 mmol) was added,and the reaction mixture was warmed to ambient temperature, then stirredfor 14 h. The reaction was quenched with water and saturatedNaHCO_(3(aq)). then extracted with DCM (3×). The combined organic layerswere washed with brine, then dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. to afford the title compound (10.6g, quantitative yield). The portion of the crude residue (1 g) waspurified directly by silica chromatography (using 9:1 to 1:1Hexanes:EtOAc as the gradient eluent) to cleanly afford the titlecompound, which was carried directly into step 2. MS (apci) m/z=188.1(M+H−Boc).

Step 2: Preparation of ethyl 4-(hydroxymethyl)piperidine-4-carboxylateHydrochloride

A solution of 1-(tert-butyl) 4-ethyl4-(hydroxymethyl)piperidine-1,4-dicarboxylate (250 mg, 0.870 mmol) inMeOH (1740 μL) was treated dropwise with 12 M HCl_((aq)) (725 μL, 8.70mmol), then stirred overnight at ambient temperature. The reactionmixture was diluted with MeOH, and concentrated in vacuo. The resultantresidue was triturated with EtOAc (5 mL) and ACN (5 mL), thenconcentrated in vacuo to cleanly afford the title compound (195 mg, 100%yield).

Intermediate R43

methyl1-(4-bromophenyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate

In a pressure vessel, a solution of methyl4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (1.99 g, 7.70mmol) in dioxane (77 mL) was treated with 1,4-dibromobenzene (5.45 g,23.1 mmol), Pd₂(dba)₃ (0.705 g, 0.770 mmol), (+)-BINAP (0.959 g, 1.54mmol) and Cs₂CO_(3(s)) (7.53 g, 23.1 mmol), then sparged with Ar_((g)).The vessel was sealed, and stirred for 16 h at 90° C. After cooling toambient temperature, the reaction mixture was diluted with EtOAc, andwashed with water (2×) and brine (1×). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Thecrude residue was purified by silica chromatography (using 5-75%Hexanes-EtOAc as the gradient eluent) to cleanly afford the titlecompound (377.4 mg, 81% yield). MS (apci) m/z=415.2 (M+2 with Brpattern).

Intermediate R44

tert-butyl (4-methyl-1-(pyridin-3-yl)piperidin-4-yl)carbamate

In a pressure tube, a suspension of 3-bromopyridine (304.9 μL, 3.165mmol), tert-butyl (4-methylpiperidin-4-yl)carbamate (678.2 mg, 3.165mmol), and Cs₂CO_(3(s)) (2.062 g, 6.329 mmol) in dioxane (15 mL) wassparged with N_(2(g)) for 5 min then treated with X-phos (150.9 mg,0.3165 mmol) and Pd₂(dba)₃ (144.9 mg, 0.1582 mmol). The resultingmixture was sparged with N_(2(g)). After sealing the vessel, thereaction mixture was stirred for 60 h at 90° C. After cooling to ambienttemperature, the resulting suspension was diluted with water (25 mL) andextracted with DCM (2×25 mL). The combined organic extracts were driedover anhydrous MgSO_(4(s)), filtered and concentrated in vacuo. Thecrude residue was purified by silica chromatography (0-50%acetone/hexanes) to afford the title compound (639.9 mg, 81% yield). MS(apci) m/z=292.2 (M+H).

Intermediate R45

tert-butyl (1-(6-bromopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

A solution of tert-butyl(4-methyl-i-(pyridin-3-yl)piperidin-4-yl)carbamate (Intermediate R44; 50mg, 0.172 mmol) in DCM (0.5 mL) was cooled to 0° C., then treated withNBS (30.5 mg, 0.172 mmol). The resulting mixture was stirred for 1 h at0° C., and then diluted with water. The biphasic mixture was extractedwith DCM (2×1 mL). The combined organic extracts were partiallyconcentrated then purified directly by silica chromatography (0-90%acetone/hexanes) to afford the title compound (50.2 mg, 79% yield). MS(apci) m/z=372.2 (M+H).

Intermediate R46

tert-butyl (1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate

In a sealed vessel, a mixture of tert-butyl(4-methylpiperidin-4-yl)carbamate (1.44 g, 6.71 mmol),2,5-dichloropyrazine (1.00 g, 6.71 mmol) and K₂CO_(3(s)) (4.64 g, 33.6mmol) in dioxane (67.1 mL) was stirred for 60 h at 60° C. After coolingto ambient temperature, the resulting suspension was diluted with EtOAc,filtered through Celite® then concentrated in vacuo. The crude residuewas purified by silica chromatography (0-100% EtOAc in hexanes) toafford the title compound (657 mg, 30% yield). MS (apci) m/z=327.1(M+H).

Intermediate R47

1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-aminebis(2,2,2-trifluoroacetate)

A mixture of tert-butyl(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (IntermediateR46; 500 mg, 1.53 mmol) in DCM (0.5 mL) was treated with TFA (0.25 mL,3.27 mmol). The resulting mixture was stirred for 2 h at ambienttemperature before concentrating the mixture in vacuo to afford thetitle compound (696 mg, quantitative yield). MS (apci) m/z=227.1 (M+H).

Intermediate R48

2-chloro-N-(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of 1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-aminebis(2,2,2-trifluoroacetate) (Intermediate R47; 596 mg, 1.31 mmol) in DCM(26 mL) was treated sequentially with 2-chloro-6-methylbenzoic acid(1.345 g, 7.89 mmol), HATU (1.999 g, 5.26 mmol) and DIEA (4.6 mL 26.3mmol). The resulting mixture was stirred overnight at ambienttemperature, before concentrating the mixture in vacuo. The cruderesidue was purified by silica chromatography (0-60% EtOAc in hexanes)to afford the title compound (360 mg, 72% yield). MS (apci) m/z=379(M+H).

Intermediate R49

2-chloro-6-methyl-N-(4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperidin-4-yl)benzamide

In a pressure vessel, a mixture of2-chloro-N-(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Intermediate R48; 730 mg, 1.92 mmol), bis(pinacolato)diboron (4.888 g,19.2 mmol), KOAc (944 mg, 9.62 mmol) and PdCl₂(dppf).CH₂Cl₂ (157 mg,0.192 mmol), in dioxane (19.25 mL) was sparged with Ar_((g)). The vesselwas sealed, and the mixture was stirred overnight at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withDCM, and filtered through a GF/F filter. The filtrate was concentratedin vacuo, and the residue was triturated with pentane (50 mL). Theresulting suspension was sonicated for 4 min, and then filtered. Thesolids were collected to afford the title compound (980 mg, 54% yield).MS (apci) m/z=389.1 (M+H).

Intermediate R50

tert-butyl(4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidin-4-yl)carbamate

In a pressure vessel, a mixture of tert-butyl(4-methylpiperidin-4-yl)carbamate (0.23 g, 1.1 mmol),2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.2g, 0.89 mmol) and K₂CO_(3(s)) (944 mg, 9.62 mmol) was combined indioxane (8.9 mL). The vessel was sealed, and the reaction mixture wasstirred overnight at 60° C. After cooling to ambient temperature, thereaction mixture was preserved as a suspension (i.e. without furtherwork up, purification or isolation) containing the title compound(assumed 370 mg, quantitative yield. MS (apci) m/z=419.3 (M+H).

Intermediate R51

6-ethoxy-4-(6-(1-tosyl-1,6-diazaspiro[2.5]octan-6-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P56, 78.5 mg, 0.200 mmol), TsCl (114 mg, 0.600 mmol), DMAP(4.89 mg, 0.0400 mmol) and TEA (139 μL, 1.00 mmol) in DCM (3 mL) wasstirred for 1.5 h at ambient temperature, before introducing additionalTsCl (38 mg, 0.20 mmol). After stirring for an additional 15 h atambient temperature, the resulting mixture was purified directly bysilica chromatography (using 0-50% EtOAc in Hexanes as the gradienteluent) to afford the title compound (55 mg, 52% yield). MS (apci)m/z=529.2 (M+H), 551.2 (M+Na).

Intermediate R52

6-ethoxy-4-(6-(1-(phenylsulfonyl)-1,6-diazaspiro[2.5]octan-6-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P56, 40 mg, 0.10 mmol), and TEA (57 μL, 0.41 mmol) in DCM(2 mL) was treated sequentially with benzenesulfonyl chloride (33 μL,0.25 mmol) and DMAP (1.2 mg, 0.01 mmol). The resulting mixture wasstirred for 22 h at ambient temperature. The reaction mixture waspurified directly by silica chromatography (0-70% EtOAc in hexanes) toafford the title compound (26 mg, 50% yield). MS (apci) m/z=515.2 (M+H),537.1 (M+Na).

Intermediate R53

Tert-butyl((3S,4S)-1-(5-chloropyrazin-2-yl)-3-hydroxypiperidin-4-yl)carbamate

A solution of 2,5-dichloropyrazine (217 mg, 1.46 mmol), tert-butyl((3S,4S)-3-hydroxypiperidin-4-yl)carbamate (300 mg, 1.387 mmol) andK₂CO₃ (575 mg, 2.25 mmol) in DMSO (2.3 mL) was stirred at 90° C. for 12h, then at room temperature overnight. The reaction was diluted withwater (15 mL) and extracted with DCM (3×15 mL). The combined organicextracts was washed with brine (15 mL), dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo. The crude waspurified by silica chromatography (0-15% MeOH/DCM) followed by reversephase chromatography (0 to 98% MeCN/water). The fractions containingproduct were combined, concentrated to remove most ACN, diluted withsat. NaHCO₃ (15 mL) and extracted with DCM (3×15 mL). The combinedorganic extracts was washed with brine (15 mL) and dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (180.7 mg, 40% yield). MS (apci) m/z=329.2 (M+H).

Intermediate R54

(S)-tetrahydrofuran-3-yl Carbonochloridate

A solution of triphosgene (111 mg, 0.375 mmol) in DCM (284 μL) wasstirred at 0° C., while sequentially adding dropwise(S)-tetrahydrofuran-3-ol (100 mg, 1.13 mmol) and a solution of pyridine(91.8 μL, 1.13 mmol) in DCM (0.15 mL). The resulting mixture was stirredfor 1.5 h at 0° C., then for an additional 0.5 h at ambient temperature.The resulting mixture was filtered to remove pyridinium solids. Thefiltrate containing the title compound in DCM was collected and used asis in subsequent steps assuming quantitative yield.

Intermediate R55

4-(2-fluorobenzyl)piperidin-4-ol hydrochloride Step 1: Preparation oftert-butyl 4-(2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate

To a solution of (2-fluorobenzyl)magnesium chloride (0.5 M in Et₂O, 2.4mL, 1.227 mmol) cooled to −78° C. was added tert-butyl4-oxopiperidine-1-carboxylate (203.7 mg, 1.022 mmol) portionwise. Thereaction mixture was allowed to gradually warm up to RT and stirredovernight. After removal of solvent under reduced pressure, the residuewas taken up in DCM and washed with water and brine. The organic layerwas concentrated and the crude material was treated with silicachromatography (0-70% EtOAc in hexanes) to yield the title compound ascolorless oil (143.9 mg, 45.5%). MS (apci) m/z=210.2 (M+H−Boc).

Step 2: Preparation of 4-(2-fluorobenzyl)piperidin-4-ol Hydrochloride

A solution of tert-butyl4-(2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate (143.9 mg, 0.4651mmol) in 1,4-dioxane (0.5 mL) was treated with conc. HCl (0.038 mL, 0.46mmol) and stirred at RT for 1 h. Removal of solvent under reducedpressure gave the title product as colorless oil (114 mg, 99% yield). MS(apci) m/z=210.1 (M+H).

Intermediate R56

4-(2-methoxybenzyl)piperidin-4-ol Hydrochloride Step 1: Preparation oftert-butyl 4-hydroxy-4-(2-methoxybenzyl)piperidine-1-carboxylate

To a solution of (2-methoxybenzyl)magnesium chloride (0.25 M in2-methyltetrahydrofuran, 4.8 mL, 1.2 mmol) cooled to −78° C. was addedtert-butyl 4-oxopiperidine-1-carboxylate (207.0 mg, 1.04 mmol)portionwise. The reaction was stirred at −78° C. for 2 h before it wasquenched with sat. NH₄Cl (aq.). After phase-separation, the aqueous wasextracted with EtOAc (3×). The organic extracts were combined, driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica chromatography (0-70% EtOAc in hexanes) to afford the titlecompound as a colorless oil (64.1 mg, 19%). MS (apci) m/z=222.2(M+H−Boc).

Step 2: Preparation of 4-(2-methoxybenzyl)piperidin-4-ol Hydrochloride

The title product (51 mg, 99%) was prepared according to the proceduredescribed for the preparation of Intermediate R55, Step 2. MS (apci)m/z=222.2 (M+H).

Intermediate R57

4-(4-fluorobenzyl)piperidin-4-ol hydrochloride Step 1: Preparation oftert-butyl 4-(4-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate

To a solution of (4-fluorobenzyl)magnesium chloride (0.5 M in2-methyltetrahydrofuran, 7.5 mL, 3.75 mmol) cooled to 0° C. was addedtert-butyl 4-oxopiperidine-1-carboxylate (496.4 mg, 2.49 mmol)portionwise. The mixture was stirred at 0° C. for 30 min before it wasquenched with sat. NH₄Cl (aq). After phase-separation, the aqueous wasextracted with EtOAc (3×). The organic extracts were combined, driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica chromatography (0-70% EtOAc in hexanes) to afford the titlecompound as a colorless oil (950.5 mg, 73%). MS (apci) m/z=210.2(M+H−Boc).

Step 2: Preparation of 4-(2-methoxybenzyl)piperidin-4-ol Hydrochloride

The title product (51 mg, 99%) was prepared according to the proceduredescribed for the preparation of Intermediate R55, Step 2. MS (apci)m/z=210.1 (M+H).

Intermediate R58

4-((6-methylpyridin-2-yl)methyl)piperidin-4-ol Step 1: Preparation oftert-butyl4-hydroxy-4-((6-methylpyridin-2-yl)methyl)piperidine-1-carboxylate

To a flask that was dried under vacuum with heat was added2,6-dimethylpyridine (0.06 mL, 0.5 mmol) and dry THF (1.1 mL) underargon. After cooling to −78° C., n-BuLi (2.5 M in THF, 0.17 mL, 0.43mmol) was introduced. The reaction was allowed to warm up to 0° C., thencooled to −78° C. again, and 1-benzylpiperidin-4-one (66 mg, 0.33 mmol)was added. The reaction was allowed to slowly warm up to RT and stirredfor 3 h before it was partitioned between DCM and water. Afterphase-separation and extracting the aqueous with DCM (2×), the organicextracts were combined, dried (Na₂SO₄), filtered and concentrated. Thecrude was purified by silica chromatography (0-20% MeOH in DCM) toafford the title compound (73 mg, 71%). MS (apci) m/z=307.2 (M+H).

Step 2: Preparation of 4-((6-methylpyridin-2-yl)methyl)piperidin-4-ol

A mixture of tert-butyl4-hydroxy-4-((6-methylpyridin-2-yl)methyl)piperidine-1-carboxylate (73mg, 0.24 mmol) in DCM (3 mL) and TFA (2 mL) was stirred at RT for 2 hbefore it was concentrated. The residue was taken up in minimal amountof MeOH and passed thru a P1-HCO₃ resin plug. Removal of solvent underreduced pressure yielded the title compound with quantitative yield. MS(apci) m/z=207.1 (M+H).

Intermediate R59

4-(3-methoxybenzyl)piperidin-4-ol hydrochloride Step 1: Preparation oftert-butyl 4-hydroxy-4-(3-methoxybenzyl)piperidine-1-carboxylate

To a solution of (3-methoxybenzyl)magnesium chloride (0.25 M in2-methyltetrahydrofuran, 15 mL, 3.75 mmol) cooled to 0° C. was addedtert-butyl 4-oxopiperidine-1-carboxylate (678 mg, 3.40 mmol)portionwise. The reaction mixture was allowed to slowly warm up to RTand stirred overnight before quenched with sat. NH₄Cl (aq.). Afterphase-separation, the aqueous was extracted with EtOAc (3×). The organicextracts were combined, dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica chromatography (0-70% EtOAc inhexanes) to afford the title compound as a colorless oil (1.09 g). MS(apci) m/z=222.2 (M+H−Boc).

Step 2: Preparation of 4-(3-methoxybenzyl)piperidin-4-ol Hydrochloride

The title product was prepared according to the procedure described forthe preparation of Intermediate R55, Step 2. MS (apci) m/z=222.1 (M+H).

RE23649-093

4-((3-chloropyridin-2-yl)methyl)piperidin-4-ol Step 1: Preparation oftert-butyl4-((3-chloropyridin-2-yl)methyl)-4-hydroxypiperidine-1-carboxylate

A solution of 3-chloro-2-methylpyridine (64.2 mg, 0.50 mmol) in THF (1mL) was sparged with N₂ and cooled to −78° C. before n-butyllithium (2.5M THF, 0.16 mL, 0.41 mmol) was added dropwise. After stirred at −78° C.for 45 min, the mixture was warmed to RT and stirred for 2 h beforecooled again to −78° C. A solution of tert-butyl4-oxopiperidine-1-carboxylate (74.2 mg, 0.37 mmol) in THF (1.5 mL) wasadded dropwise. After stirring for 2 hr at −78° C., the mixture waswarmed to rt and stirred for 2 d. The reaction was then partitionedbetween EtOAc and sat. NH₄Cl (aq). After phase-separation, the aqueouswas extracted with EtOAc (3×). The organic extracts were combined, driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica chromatography (10-90% EtOAc in hexanes) to afford the titlecompound as a colorless oil (103.5 mg, 85%). MS (apci) m/z=227.1(M+H−Boc).

Step 2: Preparation of 4-((3-chloropyridin-2-yl)methyl)piperidin-4-ol

A solution of tert-butyl4-((3-chloropyridin-2-yl)methyl)-4-hydroxypiperidine-1-carboxylate(103.5 mg, 0.32 mmol) in DCM (1.5 mL) was treated with TFA (1.5 mL) andstirred at RT overnight. After removal of solvent under reducedpressure, the residue was treated with NaHCO₃ (sat.) and extracted with4:1 DCM/IPA (4×). The combined organic extracts were passed through aphase-separator frit and concentrated to afford the title product as acolorless oil (71.1 mg, 99%). MS (apci) m/z=227.1 (M+H).

Intermediate R61

4-((5-fluoropyridin-3-yl)methyl)piperidin-4-ol Step 1: Preparation oftert-butyl4-((5-fluoropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate

A solution of 3-fluoro-5-methylpyridine (279 mg, 2.51 mmol) in THF (1.5mL) was sparged with N₂ and cooled to −78° C. before butyllithium (2.5 MTHF, 0.79 mL, 1.99 mmol) was added dropwise. After 5 min stirring, asolution of tert-butyl 4-oxopiperidine-1-carboxylate (359.7 mg, 1.805mmol) in THF (1.5 mL) was added dropwise, and stirring continued foranother 5 min. The reaction was then quenched with sat. NH₄Cl (aq) andfiltered. After phase-separation, the organic layer was washed withwater, dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by silica chromatography (10-90% EtOAc in hexanes) to affordthe title product as a colorless oil (104.9 mg, 18.7%). MS (apci)m/z=211.1 (M+H−Boc).

Step 2: Preparation of 4-((5-fluoropyridin-3-yl)methyl)piperidin-4-ol

The title product was prepared according to the procedure described forthe preparation of Intermediate R60, Step 2. MS (apci) m/z=211.2 (M+H).

The compounds in Table R1 were prepared using similar methods asdescribed for the preparation of Intermediate R56 (Method A),Intermediate R57 (Method B), Intermediate R60 (Method C), IntermediateR55 (Method D) or Intermediate R58 (Method E), using the appropriatereagent and chromatography conditions for Step 1.

TABLE R1 Inter- LCMS mediate Method Structure Chemical Name m/z R62 A

4-(3- methylbenzyl)piperidin- 4-ol hydrochloride 206.2 (M + H) R63 A

4-(4- methylbenzyl)piperidin- 4-ol hydrochloride 206.3 (M + H) R64 B

4-(2- methylbenzyl)piperidin- 4-ol hydrochloride 206.2 (M + H) R65 C

4-((5-methylpyrazin-2- yl)methyl)piperidin-4-ol 208.2 (M + H) R66 C

4-((6-methoxypyridin-3- yl)methyl)piperidin-4-ol hydrochloride 223.1(M + H) R67 D

4-(3- fluorobenzyl)piperidin-4- ol hydrochloride 210.2 (M + H) R68 E

4-((3-fluoropyridin-2- yl)methyl)piperidin-4-ol 211.2 (M + H)

Intermediate R69

1-(5-chloropyrazin-2-yl)-4-((3-chloropyridin-2-yl)methyl)piperidin-4-ol

A solution of 4-((3-chloropyridin-2-yl)methyl)piperidin-4-ol (R60, 222.0mg, 0.98 mmol) and 2,5-dichloropyrazine (145.9 mg, 0.98 mmol) in DMSO (2mL) was treated with DIEA (0.86 mL, 4.90 mmol) and stirred at 100° C.overnight. After cooling to RT the reaction was diluted with H₂O andextracted with 4:1 DCM/IPA (3×). The organic extracts were combined andconcentrated. The crude residue was purified by silica chromatography(20-80% EtOAc in hexanes) to afford the title product as a colorless oil(206.7 mg, 62% yield). MS (apci) m/z=339.1 (M+H).

Intermediate R70

1-(5-chloropyrazin-2-yl)-4-((3-fluoropyridin-2-yl)methyl)piperidin-4-ol

The title product (460 mg, 59%) was prepared according to the proceduredescribed for the preparation of Intermediate R69, replacing4-((3-chloropyridin-2-yl)methyl)piperidin-4-ol with4-((3-fluoropyridin-2-yl)methyl)piperidin-4-ol (Intermediate R68). MS(apci) m/z=323.1 (M+H).

Intermediate R71

1-(5-chloropyrazin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-ol

The title product (550 mg, 96%) was prepared according to the proceduredescribed for the preparation of Intermediate R69, replacing4-((3-chloropyridin-2-yl)methyl)piperidin-4-ol with4-(pyridin-2-ylmethyl)piperidin-4-ol dihydrochloride. MS (apci)m/z=305.1 (M+H).

Intermediate R72

4-benzyl-1-(5-chloropyrazin-2-yl)piperidin-4-amine Step 1: Preparationof 4-benzylpiperidin-4-amine bis(2,2,2-trifluoroacetate)

A mixture of tert-butyl 4-amino-4-benzylpiperidine-1-carboxylate (210mg, 0.723 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for ˜3 hbefore it was concentrated to yield the title compound assumingquantitative yield. MS (apci) m/z=191.2 (M+H).

Step 2: Preparation of4-benzyl-1-(5-chloropyrazin-2-yl)piperidin-4-amine

To a solution of 2,5-dichloropyrazine (0.1316 mL, 0.7243 mmol) in DMSO(10 mL) were added K₂CO₃ (300.3 mg, 2.173 mmol) followed by4-benzylpiperidin-4-amine bis(2,2,2-trifluoroacetate) (303 mg, 0.72mmol). The reaction was sealed and heated at 75° C. overnight. Aftercooling to RT, the reaction was diluted with EtOAc (10 mL) and water (20mL). After phase-separation, the aqueous was extracted with EtOAc (2×).The combined organic extracts were concentrated and used directly in thenext step. MS (apci) m/z=303.1 (M+H).

SYNTHETIC EXAMPLES Example 1

1-(5-(3-Cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-isopropylpiperidine-4-carboxamide

A stirred solution of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP1, Step 6 of Part B; 20 mg, 0.0793 mmol) in dioxane (33.7 mL) wastreated with(6-(4-ethyl-4-(isopropylcarbamoyl)piperidin-1-yl)pyridin-3-yl)boronicacid (Intermediate R3; 38.0 mg, 0.119 mmol) and 2 M K₂CO_(3(aq)) (79.3μL, 0.159 mmol). The mixture was purged with N_(2(g)) for 5 min, thentreated with X-Phos (7.56 mg, 0.0159 mmol) and Pd₂(dba)₃ (3.63 mg,0.00397 mmol), and purged again with N_(2(g)) for an additional 5 min.The resulting reaction mixture was stirred overnight at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withwater and the biphasic mixture was extracted with EtOAc. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. Purification of the crude residue by silicachromatography (0-10% MeOH/DCM in EtOAc as the gradient eluent) cleanlyprovided the title compound (29.2 mg, 82% yield). MS (apci) m/z=447.2(M+H).

Example 2

tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate

A suspension of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.086 g, 0.30 mmol) in DMSO (709 μL) was treated withtert-butyl (S)-piperidin-3-ylcarbamate (180 mg, 0.91 mmol) andK₂CO_(3(s)) (170 mg, 1.2 mmol) was stirred overnight at 110° C. Thereaction mixture was cooled to ambient temperature, and then dilutedwith DCM. The pH of the resulting mixture was adjusted to about pH 7with the addition of saturated NH₄Cl_((aq)). The biphasic mixture wasextracted with DCM, and the combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. The cruderesidue was purified by silica chromatography (0-15% MeOH/EtOAc as thegradient eluent) to afford the title compound (94 mg, 67% yield). MS(apci) m/z=463.3 (M+H).

Example 3

(S)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(Example 2; 10 mg, 0.0216 mmol) in DCM (500 μL) was treated with TFA(49.7 μL, 0.6486 mmol) and stirred overnight at ambient temperature. Thereaction mixture was diluted with DCM and directly purified by C18reverse phase chromatography (20-80% ACN/Water with 0.1% formic acid asthe gradient eluent) to afford the title compound (5.7 mg, 73% yield).MS (apci) m/z=363.2 (M+H).

Example 4

(S)-6-ethoxy-4-(6-(3-(methylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(TFA Salt)

Step 1: Preparation of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate2,2,2-trifluoroacetate. A solution of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(Example 2; 0.026 g, 0.0562 mmol) in DMA (250 μL) was treated with TEA(94 μL, 0.675 mmol) and a solution of iodomethane (1 drop, approximately3.5 μL, 0562 mmol) in DMA (250 μL). The reaction mixture was stirred 2 hat ambient temperature before introducing additional concentratediodomethane (2 drops, approximately 7 μL, 1.1 mmol). The reactionmixture was allowed to stir overnight at 0° C. Due to insufficientreaction progression, the reaction mixture was treated with NaH (60% inmineral oil; 3 mg, 0.125 mmol). The resulting mixture was allowed tostir 6 h at ambient temperature, and then additional concentratediodomethane (4 drops, approximately 14 μL, 2.25 mmol) was added. Thereaction mixture was stirred overnight at ambient temperature, and thenquenched with water in DCM. The resulting biphasic mixture was extractedwith DCM, and the combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo. The residue waspurified by C18 reverse phase chromatography (5-95% ACN in water with0.01% TFA as the gradient eluent) to afford the title compound as theTFA Salt (13.7 mg, 51% yield). MS (apci) m/z=477.3 (M+H).

Step 2: Preparation of(S)-6-ethoxy-4-(6-(3-(methylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate2,2,2-trifluoroacetate (step 1, 13.7 mg, 0.0288 mmol) in DCM (500 μL)was treated with TFA (22.0 μL, 0.288 mmol) was stirred for 5 h atambient temperature. The reaction mixture was diluted with MeOH (1 mL)and purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.01% TFA as the gradient eluent) to afford the titlecompound (9.7 mg, 90% yield). MS (apci) m/z=377.2 (M+H).

Example 5

(S)-4-(6-(3-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(TFA Salt)

A solution of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(Example 2; 20 mg, 0.0432 mmol) and formaldehyde (130 μL, 0.140 mmol) informic acid (326 μL) was stirred 4 h at ambient temperature and then anadditional 2 h at 90° C. Due to insufficient reaction progression, thereaction mixture was treated with NaH (60% in mineral oil; 3 mg, 0.125mmol). The resulting mixture was quenched with saturated NH₄Cl_((aq)).The resulting biphasic mixture was concentrated in vacuo. The residuewas purified by C18 reverse phase chromatography (5-95% ACN in waterwith 0.01% TFA as the gradient eluent) to afford the title compound (5.5mg, 33% yield). MS (apci) m/z=391.2 (M+H).

Example 6

tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-3-yl)(methyl)carbamate

A suspension of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.060 g, 0.21 mmol) in DMSO (1.0 mL) was treated withtert-butyl methyl((3S,4S)-4-methylpiperidin-3-yl)carbamate (97 mg, 0.43mmol) and K₂CO_(3(s)) (120 mg, 0.85 mmol) was stirred for 10 h at 90° C.The reaction mixture was cooled to ambient temperature and then quenchedwith the addition of a 1:1 mixture of water and saturated NH₄Cl_((aq)).The resulting mixture was extracted with DCM. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The crude residue was purified by C18 reversephase chromatography (20-90% ACN/water as the gradient eluent) to affordthe title compound (63 mg, 60% yield). MS (apci) m/z=491.3 (M+H).

Example 7

6-Ethoxy-4-(6-((3S,4S)-4-methyl-3-(methylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(TFA Salt)

A suspension of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-3-yl)(methyl)carbamate(Example 6; 63 mg, 0.13 mmol) in DCM (0.5 mL) was treated with TFA (98.3μL, 1.284 mmol). The reaction mixture was stirred for 5 h at ambienttemperature, and then concentrated in vacuo. The crude residue waspurified by C18 reverse phase chromatography (5-95% ACN in water with0.01% TFA as the gradient eluent) to afford the title compound as TFAsalt (41.1 mg, 82% yield). MS (apci) m/z=391.2 (M+H).

Example 8

4-(6-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A suspension of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileIntermediate P6; 87 mg, 0.31 mmol) in DMSO (3.0 mL) was treated withtert-butyl ((3R,4R)-4-hydroxypiperidin-3-yl)carbamate (200 mg, 0.92mmol) and K₂CO_(3(s)) (170 mg, 1.2 mmol) was stirred overnight at 110°C. After cooling to ambient temperature, the reaction mixture wasdiluted with DCM, and the pH of the mixture was adjusted to about pH 7with the addition of saturated NH₄Cl_((aq)). The resulting biphasicmixture was extracted with DCM. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. Thecrude residue was purified by C18 reverse phase chromatography (10-85%ACN in water with 0.01% TFA as the gradient eluent) to provide a 2:1mixture of the title compound plus the Boc protected title compound. Themixture was next purified by C18 reverse phase chromatography (5-95% ACNin water with 0.1 w/w % TFA) to afford the title compound as the TFAsalt (15 mg, 13% yield). MS (apci) m/z=379.1 (M+H).

Example 9

6-ethoxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 30 mg, 0.11 mmol), 2-(piperidin-4-yloxy)pyridine (28.4mg, 0.159 mmol), and TEA (44 μL, 0.319 mmol) in DMA (500 μL) was stirredovernight at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM and quenched with water. The resultingbiphasic mixture was extracted with DCM. The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The crude residue was purified by silica chromatography (40-100%EtOAc/Hexanes as the gradient eluent) to afford the title compound (23.6mg, 50% yield). MS (apci) m/z=441.2 (M+H).

Example 10

6-ethoxy-4-(6-(4-(pyrimidin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound (18.6 mg, 40% yield) was prepared and purified usinga similar procedure to that described for Example 9, replacing2-(piperidin-4-yloxy)pyridine with 2-(piperidin-4-yloxy)pyrimidine. MS(apci) m/z=442.3 (M+H).

Example 11

6-ethoxy-4-(6-(6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared, quenched and worked up using similarprocedures to those described for Example 6, replacing tert-butyl((3R,4R)-4-hydroxypiperidin-3-yl)carbamate with3-azabicyclo[3.1.1]heptan-6-ol. The crude residue was suspended in 19:1Et₂O:MeOH, and the resultant suspension was filtered to cleanly providethe title compound (73.2 mg, 61% yield). MS (apci) m/z=376.2 (M+H).

Example 12

6-ethoxy-4-(6-(6-(2-methoxyethoxy)-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A cold (0° C.) suspension of6-ethoxy-4-(6-(6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 11; 15 mg, 0.040 mmol) in DMA (500 μL) was treated with NaH (3mg, 0.12 mmol). The resulting mixture was allowed to warm to ambienttemperature, before introducing 1-bromo-2-methoxyethane (56 mg, 0.40mmol). After stirring for 1 hour at 90° C., the reaction mixture wascooled to ambient temperature and quenched with water. The resultingmixture was diluted with additional water and brine, and was extractedwith DCM. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo. The residue waspurified by silica chromatography (0-15% MeOH/EtOAc as the gradienteluent) to afford the title compound (7.7 mg, 44% yield). MS (apci)m/z=434.2 (M+H).

Example 13

6-ethoxy-4-(6-((rel-1R,5S,6R)-6-(pyrimidin-2-yloxy)-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A cold (0° C.) suspension of6-ethoxy-4-(6-(6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 11; 20 mg, 0.0533 mmol) in DMSO (500 μL) was treated with NaH(2.6 mg, 0.107 mmol) The resulting mixture was allowed to warm toambient temperature, and 2-chloropyrimidine (18.3 mg, 0.160 mmol) wasadded. After stirring for 0.5 h at 50° C., the reaction mixture wascooled to ambient temperature and quenched dropwise with water. Theresulting mixture was diluted with additional water and brine and thenextracted with DCM. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. The residuewas purified by silica chromatography (0-15% MeOH/EtOAc as the gradienteluent) to afford the title compound (13.9 mg, 58% yield). MS (apci)m/z=454.2 (M+H).

Example 14

6-ethoxy-4-(6-((rel-1R,5S,6R)-6-(pyridin-2-yloxy)-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared using a similar method to that describedfor Example 13, replacing 2-chloropyrimidine with 2-chloropyridine.Purification by silica chromatography (40-100% EtOAc/hexanes as thegradient eluent) cleanly provided the title compound (11.3 mg, 47%yield). (MS (apci) m/z=453.2 (M+H).

Example 15

(4-(6-(6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(TFA Salt)

Step 1: Preparation of tert-butyl(3-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate.A suspension of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.065 g, 0.23 mmol), tert-butyl(3-azabicyclo[3.1.1]heptan-6-yl)carbamate (98 mg, 0.46 mmol) andK₂CO_(3(s)) (130 mg, 0.92 mmol) in DMSO (500 μL) was stirred overnightat 90° C. The reaction mixture was diluted with DCM, and quenched withwater. The resulting biphasic mixture was diluted with additional waterand brine, and then extracted with DCM. The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The residue was purified by silica chromatography (40-100%EtOAc/hexanes as the gradient eluent) to afford the title compound (7.3mg, 67% yield). MS (apci) m/z=475.2 (M+H).

Step 2: Preparation of4-(6-(6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate. A solution of tert-butyl(3-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate(90 mg, 0.1896 mmol) in DCM (1.25 mL) was treated with TFA (581 μL, 7.59mmol) and stirred overnight at ambient temperature. The reaction mixturewas concentrated in vacuo, and the residue was purified by C18 reversephase chromatography (5-95% ACN in water with 0.01% TFA as the gradienteluent) to afford the title compound as TFA salt (8.72 mg,). MS (apci)m/z=375.2 (M+H).

Example 16

6-ethoxy-4-(6-((rel-1R,5S,6S)-6-((6-methoxypyridin-3-yl)amino)-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 64.4 mg, 0.228 mmol),N-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.1]heptan-6-amine2,2,2-trifluoroacetate (Intermediate R8; 25 mg, 0.114 mmol) in DMSO (500μL) was treated with K₂CO_(3(s)) (63.0 mg, 0.456 mmol) and stirredovernight at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM and quenched with water. The resultingbiphasic mixture was extracted with DCM. The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The crude residue was purified by silica chromatography (40-100%EtOAc/hexanes as the gradient eluent) to afford the title compound (10.2mg, 19% yield). MS (apci) m/z=482.3 (M+H).

Example 17

(S)-6-(2-hydroxyethoxy)-4-(6-(3-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P26; 30 mg, 0.073 mmol) in DMSO (1.5 mL) was treated with(S)-3-hydroxypiperidine hydrochloride (0.050 g, 0.36 mmol) andK₂CO_(3(s)) (40 mg, 0.29 mmol) and stirred 2 h at 110° C. After coolingto ambient temperature, the reaction mixture was quenched with water.The resultant suspension was filtered, and the isolated solids werepurified by silica chromatography (0-20% MeOH in DCM as the gradienteluent) to afford the title compound (7.5 mg, 27% yield). MS (apci)m/z=380.1 (M+H).

Example 18

(S)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P26; 60 mg, 0.15 mmol) in DMSO (2.9 mL) was treated with(S)-3-(tert-butoxycarbonylamino)piperidine (0.12 g, 0.58 mmol) andK₂CO_(3(s)) (80 mg, 0.58 mmol) and stirred for 1 hour at 110° C. Aftercooling to ambient temperature, the reaction mixture was neutralizedwith the addition 1 M HCl_((aq)). The resultant suspension was extractedwith DCM, and the organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (0-10% MeOH in DCM as the gradienteluent) to afford the Boc-protected title compound. The Boc-protectedmaterial was dissolved in DCM (3 mL) then treated with 4 N HCl indioxanes (3 mL). After stirring overnight at ambient temperature, thereaction mixture was concentrated in vacuo. The residue was purified bysilica chromatography (0-100% [20% MeOH, 2% NH₄OH, 78% DCM] in DCM asthe gradient eluent) to cleanly provide the title compound (20 mg, 35%yield). MS (apci) m/z=379.2 (M+H).

Example 19

tert-butyl(1-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P26; 111 mg, 0.269 mmol) and tert-butylN-(4-methyl-4-piperidyl)carbamate (173 mg, 0.807 mmol) in DMSO (2.5 mL)was stirred for 1 hour at 110° C. After cooling to ambient temperature,the reaction mixture was quenched with water. The resultant suspensionwas filtered, and the solids were collected to cleanly provide the titlecompound (65 mg, 49% yield). MS (apci) m/z=493.2 (M+H).

Example 20

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Example 19; 45 mg, 0.091 mmol) in DCM (2 mL) was treated with 4 N HClin dioxanes (3 mL, 12 mmol) and stirred for 2 h at ambient temperature.The resultant mixture was concentrated in vacuo to afford the titlecompound as the HCl salt. The salt was dissolved in MeOH, filteredthrough an Agilent PL-HCO3 MP SPE filter (to neutralize the HCl salt),and concentrated in vacuo to cleanly provide the title compound (30 mg,84% yield). MS (apci) m/z=393.2 (M+H).

Example 21

N-(1-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-methylbutanamide

A solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 20; 15 mg, 0.038 mmol) in DCM (191 μL) was treated sequentiallywith DIEA (20 μL, 0.11 mmol) and isovaleryl chloride (5.1 μL, 0.042mmol) and stirred overnight at ambient temperature. The reaction mixturewas concentrated in vacuo, and the residue was purified by silicachromatography (0-20% MeOH in DCM as the gradient eluent) to cleanlyprovide the title compound (4.8 mg, 26% yield). MS (apci) m/z=477.2(M+H).

Example 22

N-(1-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)isobutyramide

The title compound was prepared using a similar procedure to thatdescribed for Example 21, replacing isovaleryl chloride with isobutyrylchloride and using 5 equivalents of DIE. Following purification bysilica chromatography (0-20% MeOH in DCM as the gradient eluent), thetitle compound was cleanly isolated (3.8 mg, 21% yield). MS (apci)m/z=463.2 (M+H).

Example 23

Isobutyl(1-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

The title compound was prepared using a similar procedure to thatdescribed for Example 21, replacing isovaleryl chloride with isobutylchloroformate (1 equivalent). Following purification by silicachromatography (0-20% MeOH in DCM as the gradient eluent), the titlecompound was cleanly isolated (6.6 mg, 35% yield). MS (apci) m/z=493.2(M+H).

Example 24

(R)-N-(1-(5-(3-cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-hydroxy-3-methylbutanamide

A solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 20; 15 mg, 0.038 mmol) in DCM (764 μL) was treated(R)-2-hydroxy-3-methylbutanoic acid (5.42 mg, 0.0459), HATU (17.4 mg,0.0459 mmol) and DIEA (26.6 μL, 0.153 mmol), and stirred overnight atambient temperature. The mixture was concentrated in vacuo, and thenpurified by silica chromatography (0-20% MeOH in DCM as the gradienteluent) to afford the title compound contaminated with DIEA. The impureresidue was partitioned between MTBE and saturated NH₄Cl_((aq)). Thecombined organic extracts were concentrated in vacuo to cleanly providethe title compound (1.6 mg, 9% yield). MS (apci) m/z=493.2 (M+H).

Example 25

1-(1-(5-(3-Cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-isopropylurea

A solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 20; 15 mg, 0.038 mmol) in anhydrous DMA (191 μL) was treatedsequentially with DIEA (20.0 μL, 0.115 mmol) and isopropyl isocyanate(3.78 μL, 0.0382 mmol). After stirring overnight at ambient temperature,the reaction mixture was purified directly by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to cleanly provide the title compound as a TFA salt. The salt wasdissolved in MeOH, filtered through an Agilent PL-HCO3 MP SPE tube toneutralize, and the filtrate was concentrated in vacuo to cleanlyprovide the title compound (4.15 mg, 23% yield). MS (apci) m/z=478.2(M+H).

Example 26

1-(1-(5-(3-Cyano-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-isobutylurea

The title compound (2.0, 11% yield) was prepared, purified andneutralized using a similar procedure to that described for Example 25,replacing isopropyl isocyanate with 1-isocyanato-2-methylpropane. MS(apci) m/z=492.3 (M+H).

Example 27

4-(6-(4-benzyl-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 29.3 mg, 0.0898 mmol), 4-benzylpiperidin-4-ol (25.8mg, 0.135 mmol) and TEA (37.5 μL, 0.269 mmol) in DMA (599 μL) wasstirred overnight at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with water and washed with DCM. The organicextracts were washed with brine, then dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was purified by C18reverse phase chromatography (5-95% water:ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was dissolved in DCM and washed with saturated Na₂CO_(3(aq)). Theorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to cleanly provide thetitle compound (22.4 mg, 50% yield). MS (apci) m/z=498.2 (M+H).

Example 28

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound (10.8 mg, 28% yield) was prepared and purified usinga similar procedure to that described for Example 27, replacing4-benzylpiperidin-4-ol with 4-methylpiperidin-4-ol. MS (apci) m/z=422.1(M+H).

Example 29

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 36 mg, 0.0856 mmol), benzoic acid (20.9 mg, 0.171mmol) and HATU (35.8 mg, 0.0942 mmol) in DCM (856 μL) was treated withDIEA (74.8 μL, 0.428 mmol) and then stirred for 2 h at ambienttemperature. The reaction mixture was concentrated in vacuo. The residuewas suspended in 60:40 ACN:water containing 2% TFA, then filteredthrough a syringe filter. The filtrate was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with DCM.The combined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (33.2 mg, 74% yield). MS (apci) m/z=525.25 (M+H).

The compounds in Table N were prepared using a similar method to thatdescribed for the synthesis of Example 29, replacing benzoic acid withthe appropriate carboxylic acid. Reactions were monitored for completionby LCMS, and reaction durations were adjusted accordingly. Titlecompounds were cleanly isolated following chromatographic purificationusing an appropriate gradient eluent (and if necessary converted to thefree base).

TABLE N MS (apci) Ex # Structure Chemical Name m/z 30

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)isobutyramide491.3 (M + H) 31

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-6-methoxynicotinamide 556.3 (M + H)

Example 32

3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropyl-3-azabicyclo[3.1.1]heptane-6-carboxamide

A mixture of3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylicacid (Intermediate P47; 32 mg, 0.072 mmol), propan-2-amine (11.7 μL,0.143 mmol) and HATU (29.9 mg, 0.358 mmol) in DCM (715 μL) was treatedwith DIEA (62.4 μL, 0.358 mmol) and then stirred overnight at ambienttemperature. The reaction mixture was concentrated in vacuo. The residuewas purified by silica chromatography (1-6% MeOH in DCM as the gradienteluent) to afford the title compound (8.3 mg, 24% yield). MS (apci)m/z=489.3 (M+H).

The compounds in Table O were prepared using a similar method to thatdescribed for the synthesis of Example 32, replacing propan-2-amine withthe appropriate amine. Reactions were monitored for completion by LCMS,and reaction durations were adjusted accordingly. Title compounds werecleanly isolated following chromatographic purification using anappropriate gradient eluent.

TABLE O MS (apci) Ex # Structure Chemical Name m/z 33

3-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N- phenyl-3- azabicyclo[3.1.1]heptane- 6-carboxamide523.2 (M+H) 34

3-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N- (6-methoxypyridin- 3-yl)-3-azabicyclo[3.1.1]heptane- 6-carboxamide 554.25 (M+H)

Example 35

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 29.7 mg, 0.0910 mmol), 2-(piperidin-4-yloxy)pyridine(24.3 mg, 0.137 mmol) and TEA (38.1 μL, 0.273 mmol) in DMA (607 μL) wasstirred overnight at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with water and washed with DCM. The organicextracts were washed with brine, then dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was purified by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was dissolved in DCM and washed with saturated Na₂CO_(3(aq)). Theorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to cleanly provide thetitle compound (12.1 mg, 27% yield). MS (apci) m/z=485.2 (M+H). ¹H NMR(400 MHz, CDCl₃) δ: 8.34 (d, 1H), 8.20 (s, 1H), 8.15 (m, 2H), 7.71 (dd,1H), 7.58 (m, 1H), 7.15 (d, 1H), 6.86 (m, 1H), 6.81 (d, 1H), 6.74 (d,1H), 5.35 (m, 1H), 4.06 (m, 2H), 3.86 (s, 2H), 3.55 (m, 2H), 2.15 (m,2H), 1.88 (m, 2H), 1.40 (s, 6H).

The compounds in Table P were prepared using a similar method to thatdescribed for the synthesis of Example 35, replacing2-(piperidin-4-yloxy)pyridine with the appropriate piperidine. Reactionswere monitored for completion by LCMS, and reaction durations wereadjusted accordingly.

TABLE P MS (apci) Ex # Structure Chemical Name m/z 36

6-(2-hydroxy-2- methylpropoxy)-4-(6- (4-(pyridin-3- yloxy)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile 485.2 (M + H)37

4-(6-(4-(4- fluorophenoxy)piperidin- 1-yl)pyridin-3-yl)- 6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3- carbonitrile 502.2 (M + H) 38

6-(2-hydroxy-2- methylpropoxy)-4-(6- (4-phenoxypiperidin-1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile 484.2 (M +H) 39

6-(2-hydroxy-2- methylpropoxy)-4-(6- (4- (phenylamino)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile 483.2 (M +H) 40

6-(2-hydroxy-2- methylpropoxy)-4-(6- (4-(pyridin-2-ylmethyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 483.2 (M + H) 41

4-(6-(4- benzylpiperidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3- carbonitrile 482.2 (M + H)

Example 42

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 2-methoxy-5-(piperidin-4-yloxy)pyridine (Intermediate R13;66.1 mg, 0.317 mmol) in DMA (794 μL) was treated with4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 51.8 mg, 0.159 mmol), and TEA (43.4 μL, 0.317 mmol).The resulting mixture was sparged with Ar_((g)) then stirred overnightat 110° C. After cooling to ambient temperature, the reaction mixturewas diluted with DCM and washed with saturated NaHCO_(3(aq)), and brine.The combined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was purified by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was dissolved in DCM and washed with saturated NaHCO_(3(aq)). Theaqueous extracts were back extracted with DCM. The combined organicextracts were washed with brine, and subsequently dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to cleanly provide thetitle compound (41 mg, 50% yield). MS (apci) m/z=515.2 (M+H).

Example 43

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-phenoxyazetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 42.7 mg, 0.131 mmol), 3-phenoxyazetidine (23.4 mg,0.157 mmol) and TEA (54.7 μL, 0.393 mmol) in DMA (872 L) was stirredovernight at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with water and washed with DCM. The organic extractswere washed with brine and dried over anhydrous Na₂SO_(4(s)), filteredand concentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was dissolvedin DCM and washed with saturated Na₂CO_(3(aq)). The combined organicextracts were washed with brine, then dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo to cleanly provide the title compound(14.1 mg, 24% yield). MS (apci) m/z=456.2 (M+H).

Example 44

6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.030 g, 0.11 mmol), triethylamine (0.044 mL, 0.32mmol) and 4-(pyridin-2-ylmethyl)piperidin-4-ol (0.041 g, 0.21 mmol) werecombined in DMA (0.5 mL) and stirred at 90° C. for 5 h. The reactionmixture was diluted with DCM (5 mL), sat. NH₄Cl (aq., 5 mL) and water(20 mL). After phase-separation, the aqueous layer was extracted withDCM. The combined organic extracts were dried (Na₂SO₄), filtered,concentrated and purified by silica chromatography (30-100%EtOAc/hexanes) to provide the title product as solid (0.022 g, 46%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.5 (dq, 1H), 8.3 (d, 1H), 8.15 (s,1H), 8.05 (d, 1H), 7.65 (qd, 2H), 7.15 (qd, 1H), 7.1 (d, 1H), 7.05 (d,1H), 6.75 (d, 1H), 6.05 (br s, 1H), 4.1 (q, 2H), 3.45 (m, 2H), 2.9 (s,2H), 1.6 (m, 4H), 1.5 (t, 3H). LCMS (apci) m/z=455.2 (M+H).

Example 45

4-(6-((3S,4S)-3-amino-4-((5-fluoro-6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1:

Preparation of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate.6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.22 g, 0.76 mmol), N-ethyl-N-isopropylpropan-2-amine(0.66 mL, 3.81 mmol), and tert-butyl((3S,4R)-4-hydroxypyrrolidin-3-yl)carbamate (0.23 g, 1.14 mmol) werecombined in DMSO (1.5 mL) and stirred at 100° C. for 60 h. The reactionmixture was diluted with sat. NH₄Cl and extracted into DCM. The combinedorganic extracts were dried (Na₂SO₄), filtered, concentrated in vacuoand purified by silica chromatography (0-100% EtOAc/hexanes) to providethe product as solid (0.28 g, 80% yield).

Step 2:

Preparation of4-(6-((3S,4S)-3-amino-4-((5-fluoro-6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A mixture of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(0.030 g, 0.07 mmol), 5-fluoro-6-methoxypyridin-3-ol (0.037 g, 0.26mmol), and triphenylphosphine (0.068 g, 0.26 mmol) was combined in 1:1DCM/THF (0.7 mL). The reaction vessel was sparged with argon, anddiisopropyl (E)-diazene-1,2-dicarboxylate (0.035 mL, 0.26 mmol) wasadded. The reaction was stirred at room temperature for 48 h. Thereaction mixture was diluted with DCM and H₂O, filtered through phaseseparating paper, and extracted into DCM. The combined organic extractswere dried (Na₂SO₄), filtered, concentrated in vacuo and purified bysilica chromatography (0-100% EtOAc/hexanes). The fractions containingthe Boc-protected title compound were concentrated, and the residue wasdiluted with 6 mL 1:1 DCM/5N HCl in isopropyl alcohol. This mixture wasstirred at room temperature 24 h. The combined organic extracts werewashed with 2M NaOH and purified by reverse phase chromatography (0-80%ACN/Water [0.1% Formic Acid]) to provide the title compound (2.2 mg,7.0% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.4 (d, 1H), 8.3 (s, 1H), 8.25(dd, 1H), 7.75 (dd, 1H), 7.7 (d, 1H), 7.3 (dd, 1H), 7.2 (d, 1H), 6.7(dd, 1H), 4.1 (m, 2H), 3.95 (s, 3H), 3.9 (m, 2H), 3.7 (dd, 1H), 3.6 (dd,1H), 3.3 (s, 2H), 1.45 (t, 3H). LCMS (apci) m/z=490.1 (M+H).

Example 46

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.040 g, 0.12 mmol) (Intermediate P42), 2-(azetidin-3-yloxy)pyridinedihydrochloride (0.055 g, 0.24 mmol) and triethylamine (0.10 mL, 0.74mmol) in DMA (0.82 mL) was heated in a sealed vial to 90° C. overnight.After cooling to ambient temperature, the reaction was partitionedbetween DCM and water (10 mL each). After phase-separation, the aqueouswas extracted with DCM (2×10 mL). The combined organic extracts waswashed with brine, dried (Na₂SO₄), filtered and concentrated. The crudewas purified by preparative HPLC (5-95% ACN in water with 0.1% TFA) toyield the title product as a TFA salt, which was then converted to thefree base by partitioning in DCM and Na₂CO₃ (sat. aq). The combinedorganic extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated to yield the title product (4.7 mg, 8.4% yield). ¹H NMR(CDCl₃) δ 8.31 (dd, 1H), 8.19 (s, 1H), 8.14 (m, 2H), 7.68 (dd, 1H), 7.61(m, 1H), 7.13 (d, 1H), 6.91 (m, 1H), 6.80 (m, 1H), 6.44 (dd, 1H), 5.57(m, 1H), 4.55 (m, 2H), 4.15 (m, 2H), 3.86 (s, 2H), 1.39 (s, 6H). LCMS(apci) m/z=457.2 (M+H).

Example 47

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.031 g, 0.095 mmol) (Intermediate P42),3-methoxy-6-(piperidin-4-yloxy)pyridazine dihydrochloride (0.090 g, 0.32mmol), triethylamine (0.10 mL, 0.76 mmol) in DMA (0.32 mL) was heated ina sealed vial to 95° C. overnight. After cooling to ambient temperature,the reaction mixture was diluted with DCM (10 mL) and sequentiallywashed with sat. NaHCO₃ (15 mL), water (2×15 mL) and brine (15 mL), thendried (Na₂SO₄), filtered and concentrated. The crude material waspurified by C18 reverse phase chromatography (5-95% ACN in water with0.01% TFA) and the combined product fractions was concentrated andconverted to the free base with sat. NaHCO₃ (15 mL). The aqueous layerwas extracted with DCM (3×15 mL). The combined organic extracts werewashed with brine (15 mL), dried (Na₂SO₄), filtered and concentrated toafford the title compound as a white solid (22.5 mg, 46% yield). ¹H NMR(CDCl₃) δ 8.32 (dd, 1H), 8.19 (s, 1H), 8.13 (d, 1H), 7.68 (dd, 1H), 7.13(d, 1H), 6.92 (m, 2H), 6.80 (m, 1H), 5.42 (m, 1H), 4.10 (m, 2H), 4.04(s, 3H), 3.84 (s, 2H), 3.46 (m, 2H), 2.22 (m, 2H), 1.88 (m, 2H), 1.39(s, 6H). LCMS (apci) m/z=516.2 (M+H).

Example 48

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-phenylpiperidine-4-carboxamide

A solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(25 mg, 0.077 mmol) (Intermediate P42),4-methyl-N-phenylpiperidine-4-carboxamide (66.9 mg, 0.31 mmol) andtriethylamine (104 μL, 0.77 mmol) in DMA (0.4 mL) was heated in a sealedvessel at 80° C. for 32 h. The reaction was then cooled to roomtemperature, diluted with EtOAc and washed with water and brine. Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was purified by preparativeHPLC (5 to 95% ACN in water with 0.1% TFA) to provide the title productas a TFA salt, which was converted to the free base by partitioningbetween 20% IPA in DCM and NaHCO₃ (sat. aq). After phase-separation, theaqueous layer was extracted with DCM. The combined organic extracts weredried (Na₂SO₄), filtered, and concentrated under vacuum to afford thetitle product as white solid (23.7 mg, 56% yield). LCMS (apci) m/z=525.2(M+H). ¹H NMR (400 MHz, d₆-DMSO) δ 9.38 (s, 1H), 8.66-8.65 (d, 1H), 8.57(s, 1H), 8.33-8.32 (d, 1H), 7.77-7.74 (dd, 1H), 7.66-7.64 (m, 2H),7.32-7.28 (m, 3H), 7.07-7.03 (m, 1H), 6.98-6.96 (d, 1H), 4.70 (s, 1H),3.95-3.87 (m, 4H), 3.42-3.36 (m, 2H), 2.23-2.19 (m, 2H), 1.58-1.52 (m,2H), 1.30 (s, 3H), 1.22 (s, 6H).

Example 49

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(isobutylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(27.2 mg, 0.083 mmol) (Intermediate P42) and4-(isobutylsulfonyl)piperidine (51.3 mg, 0.25 mmol) were dissolved inDMA (0.5 mL, 0.15 M) at room temperature. The reaction mixture wastreated with triethylamine (56 μL, 0.42 mmol), sealed, and heated at 80°C. for 36 h. The reaction mixture was then cooled to room temperature,diluted with ethyl acetate and washed with water and brine. The combinedorganic extracts were dried over Na₂SO₄, filtered, and concentrated invacuo. The crude material was purified by preparative HPLC (5 to 95% ACNin water with 0.1% TFA) to provide the product as a TFA salt, which wasconverted to the free base by partitioning between 20% IPA in DCM andNaHCO₃ (sat. aq). After phase separation, the aqueous layer wasextracted with DCM. The combined organic extracts were dried (Na₂SO₄),filtered, and concentrated under vacuum to afford the title product as awhite solid (20 mg, 47% yield). LCMS (apci) m/z=512.2 (M+H). ¹H-NMR (400MHz, d₆-DMSO) δ 8.67-8.66 (d, 1H), 8.57 (s, 1H), 8.35-8.34 (d, 1H),7.81-7.78 (dd, 1H), 7.32-7.31 (d, 1H), 7.03-7.01 (d, 1H), 4.70 (s, 1H),4.57-4.54 (m, 2H), 3.87 (s, 2H), 3.46-3.36 (m, 1H), 3.01-2.93 (m, 4H),2.29-2.19 (m, 1H), 2.10-2.06 (m, 2H), 1.64-1.53 (m, 2H), 1.22 (s, 6H),1.07-1.03 (m, 7H).

Example 50

4-(6-(4-((5-fluoro-2-methylbenzyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.119 mmol) in DCM (1 mL) was added DIEA (73μL, 0.416 mmol). The solution stirred for 10 min at ambient temperature.5-Fluoro-2-methylbenzaldehyde (29 μL, 0.238 mmol) was added, followed byNaBH(AcO)₃ (76 mg, 0.357 mmol) The resulting reaction mixture wasallowed to stir 12 h at ambient temperature. The reaction was dilutedwith DCM and washed with saturated NaHCO_(3(aq)). The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(1-10% MeOH in DCM with 0.1-1% NH₄OH as the gradient eluent) to cleanlyprovide the title compound (25 mg, 39% yield). MS (apci) m/z=543.3 (M+H)

Example 51

4-(6-(4-(benzylamino)-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.119 mmol) in DCM (1 mL) was added DIEA (73μL, 0.416 mmol). The solution stirred for 10 min at ambient temperature.Then benzaldehyde (25 mg, 0.238 mmol) was added, followed by NaBH(AcO)₃(76 mg, 0.357 mmol) The resulting reaction mixture was allowed to stir12 h at ambient temperature. The reaction was diluted with DCM andwashed with saturated NaHCO_(3(aq)). The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was purified by silica chromatography (1-10% MeOH in DCMwith 0.1-1% NH₄OH as the gradient eluent) to cleanly provide the titlecompound (27 mg, 45% yield) MS (apci) m/z=511.3 (M+H)

Example 52

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-(trifluoromethyl)benzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.12 mmol), HATU (50 mg, 0.13 mmol), and2-(trifluoromethyl)benzoic acid (25 mg, 0.13 mmol) in DMSO (1 mL) wastreated with DIEA (83 μL, 0.48 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was concentrated in vacuo. Thereaction mixture was diluted with EtOAc and washed with water. Theorganic extracts then dried over anhydrous MgSO_(4(s)), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(1-10% MeOH in DCM with 0.1-1% NH₄OH as the gradient eluent) to cleanlyprovide the title compound (37 mg, 53% yield) MS (apci) m/z=593.3 (M+H).

The compounds in Table Q were prepared using a similar method to thatdescribed for the synthesis of Example 52, replacing2-(trifluoromethyl)benzoic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE Q LCMS Ex. # Structure Chemical Name m/z 53

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-fluoro-2-methylbenzamide 557.3 (M + H) 54

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-2,3-difluorobenzamide 561.3 (M + H) 55

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-5-fluoro-2-(trifluoromethyl)benzamide 611.3 (M + H)

Example 56

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-fluoro-6-methylbenzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.12 mmol), HATU (90 mg, 0.24 mmol), and2-Fluoro-6-methylbenzoic acid (37 mg, 0.24 mmol) in DMSO (1 mL) wastreated with DIEA (93 μL, 0.54 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was concentrated in vacuo. Thereaction mixture was diluted with EtOAc and washed with water. Theorganic extracts were dried over anhydrous MgSO_(4(s)), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(1-10% MeOH in DCM with 0.1-1% NH₄OH as the gradient eluent) to cleanlyprovide the title compound (35 mg, 53% yield) MS (apci) m/z=557.3 (M+H).

The compounds in Table R were prepared using a similar method to thatdescribed for the synthesis of Example 56, replacing2-Fluoro-6-methylbenzoic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE R LCMS Ex. # Structure Chemical Name m/z 57

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3,4-difluorobenzamide 561.3 (M + H) 58

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2,6-dimethylisonicotinamide 554.3 (M + H)

Example 59

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)pyrimidine-4-carboxamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 43 mg, 0.10 mmol), HATU (77.8 mg, 0.21 mmol), andpyrimidine-4-carboxylic acid (12.7 mg, 0.10 mmol) in DMSO (600 μL) wastreated with DIEA (80 μL, 0.46 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts then dried over anhydrousMgSO_(4(s)), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (1-10% MeOH in DCM with 0.1-1% NH₄OHas the gradient eluent) to cleanly provide the title compound (35 mg,53% yield). MS (apci) m/z=527.3 (M+H).

Example 60

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3,4-difluorobenzamide

The compound was prepared using a similar method to that described forthe synthesis of Example 59, replacing pyrimidine-4-carboxylic acid withpyrazine-2-carboxylic acid. MS (apci) m/z=527.2 (M+H).

Example 61

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 35 mg, 0.08 mmol), HATU (34.8 mg, 0.09 mmol), andpicolinic acid (22.6 mg, 0.18 mmol) in DCM (832 μL) was treated withDIEA (47 μL, 0.35 mmol) and then stirred for 18 h at ambienttemperature. The reaction mixture was concentrated in vacuo. The residuewas suspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (43.7 mg, 49.3% yield). MS (apci)m/z=526.20 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.54 (m, 1H), 8.33 (d, 1H),8.19 (s, 1H), 8.18 (dt, 1H), 8.16 (s, br, 1H), 8.14 (d, 1H), 7.85 (td,1H). 7.70 (dd, 1H), 7.43 (m, 1H), 7.13 (d, 1H), 6.80 (d, 1H), 4.08 (m,2H), 3.85 (s, 2H), 3.37 (m, 2H), 2.42 (m, 2H), 1.82 (m, 2H), 1.59 (s,3H), 1.39 (s, 6H)

Example 62

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 15.8 mg, 0.038 mmol), HATU (15.7 mg, 0.041 mmol), and5-Fluoro-2-methylbenzoic acid (11.6 mg, 0.075 mmol) in DCM (1.07 mL) wastreated with DIEA (33 μL, 0.19 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (11.2 mg, 53.6% yield). MS (apci)m/z=557.3 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, 1H), 8.20 (s, 1H),8.15 (d, 1H), 7.71 (dd, 1H), 7.17 (dd, 1H). 7.14 (d, 1H), 7.06 (dd, 1H),7.00 (td, 1H), 6.81 (d, 1H), 5.50 (s, br, 1H), 4.01 (m, 2H), 3.86 (s,2H), 3.41 (m, 2H), 2.41 (s, 3H), 2.30 (m, 2H), 1.84 (m, 2H), 1.61 (s,3H), 1.39 (s, 6H)

The compounds in Table S were prepared using a similar method to thatdescribed for the synthesis of Example 62, replacing5-Fluoro-2-methylbenzoic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE S LCMS Ex. # Structure Chemical Name m/z 63

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)pyridazine-3-carboxamide 527.20 (M + H) 64

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3,5-difluorobenzamide 561.2 (M + H) 65

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-fluorobenzamide543.2 (M + H) 66

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-methylbenzamide539.3 (M + H) 67

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-cyclopropylbenzamide 565.3 (M + H) 68

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-2-methoxybenzamide 555.3 (M + H) 69

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3-methoxybenzamide 555.3 (M + H) 70

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-cyclopropylbenzamide 565.3 (M + H) 71

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-6-methoxypicolinamide 556.3 (M + H) 72

3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-methylbenzamide573.3 (M + H) 73

5-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-methylbenzamide573.3 (M + H) 74

2-cyano-N-(1-(5-(3-cyano- 6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)benzamide 550.3(M + H) 75

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-ethylbenzamide553.3 (M + H) 76

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-(methylsulfonyl)benzamide 603.3 (M + H) 77

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-fluorobenzamide543.3 (M + H)

Example 78

3-chloro-N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.12 mmol), HATU (50 mg, 0.13 mmol), and3-chloropicolinic acid (37 mg, 0.24 mmol) in DMSO (1.2 mL, 0.1 M) wastreated with DIEA (100 μL, 0.59 mmol) and then stirred for 1 h atambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was suspended in 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (45 mg, 68% yield).MS (apci) m/z=560.2 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (dd, 1H), 8.32(d, 1H), 8.18 (s, 1H), 8.12 (d, 1H), 7.88 (s, br, 1H), 7.81 (dd, 1H).7.68 (dd, 1H), 7.35 (dd, 1H), 7.11 (d, 1H), 6.78 (d, 1H), 4.06 (m, 2H),3.85 (s, 2H), 3.36 (m, 2H), 2.38 (m, 2H), 1.79 (m, 2H), 1.60 (s, 3H),1.38 (s, 6H).

Example 79

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-(trifluoromethyl)picolinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.12 mmol), HATU (50 mg, 0.13 mmol), and3-(trifluoromethyl)picolinic acid (45.4 mg, 0.24 mmol) in DMSO (1.19 mL,0.1 M) was treated with DIEA (104 μL, 0.60 mmol) and then stirred for 18h at ambient temperature. The reaction mixture was diluted with EtOAcand washed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was suspended in 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (46.5 mg, 66% yield).MS (apci) m/z=594.3 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.8.71 (d, 1H),8.34 (d, 1H), 8.19 (s, 1H), 8.16 (d, 1H), 8.14 (d, 1H), 7.70 (dd, 1H).7.56 (dd, 1H), 7.52 (s, br, 1H), 7.13 (d, 1H), 6.80 (d, 1H), 4.06 (m,2H), 3.85 (s, 2H), 3.36 (m, 2H), 2.40 (m, 2H), 1.82 (m, 2H), 1.60 (s,3H), 1.39 (s, 6H).

Example 80

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2,6-difluorobenzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.12 mmol), HATU (50 mg, 0.13 mmol), and2,6-difluorobenzoic acid (37.6 mg, 0.24 mmol) in DMSO (1.19 mL, 0.1 M)was treated with DIEA (104 μL, 0.60 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was suspended in 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (46.5 mg, 66% yield).MS (apci) m/z=561.2 (M+H).

Example 81

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2,5-difluorobenzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 67 mg, 0.16 mmol), HATU (67 mg, 0.18 mmol), and2,5-difluorobenzoic acid (50 mg, 0.32 mmol) in DMSO (1.6 mL, 0.1 M) wastreated with DIEA (0.14 mL, 0.80 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was suspended in 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (57 mg, 64% yield).MS (apci) m/z=561.2 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, 1H), 8.20(s, 1H), 8.14 (d, 1H), 7.76 (m, 1H). 7.70 (dd, 1H), 7.14 (m, 3H), 6.80(d, 1H), 6.62 (d, 1H), 4.06 (m, 2H), 3.86 (s, 2H), 3.34 (m, 2H), 2.31(m, 2H), 1.81 (m, 2H), 1.59 (s, 3H), 1.39 (s, 6H).

The compounds in Table T were prepared using a similar method to thatdescribed for the synthesis of Example 81, replacing 2,5-difluorobenzoicacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent (and if necessaryconverted to the free base).

TABLE T LCMS Ex. # Structure Chemical Name m/z 82

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-6-ethylpicolinamide 554.3 (M + H) 83

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3-fluoropicolinamide 544.3 (M + H) 84

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-methoxypicolinamide 556.3 (M + H) 85

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)pyrimidine-2-carboxamide 527.2 (M + H) 86

3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)benzamide559.2 (M + H)

Example 87

5-chloro-N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-methylnicotinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 53 mg, 0.107 mmol), HATU (44.9 mg,0.118 mmol), and 5-Chloro-2-methyl-3-pyridinecarboxylic acid (36.9 mg,0.107 mmol) in DMSO (1.28 mL, 0.1 M) was treated with DIEA (0.09 mL,0.54 mmol) and then stirred for 18 h at ambient temperature. Thereaction mixture was diluted with EtOAc and washed with water. Theorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The residue wassuspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (26.1 mg, 42% yield). MS (apci)m/z=574.2 (M+H).

Example 88

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3,6-dimethylpicolinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 63 mg, 0.128 mmol), HATU (67 mg, 0.18mmol), and 3,6-Dimethylpicolinic acid (38.6 mg, 0.26 mmol) in DMSO (1.28mL, 0.1 M) was treated with DIEA (0.11 mL, 0.64 mmol) and then stirredfor 18 h at ambient temperature. The reaction mixture was diluted withEtOAc and washed with water. The organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo. The residue was suspended in 60:40 ACN:water containing 2%TFA. The solution was purified directly by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO_(3(aq)) and extracted with DCM. The combinedorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (57 mg, 64% yield). MS (apci) m/z=554.3 (M+H).

The compounds in Table U were prepared using a similar method to thatdescribed for the synthesis of Example 88, replacing3,6-Dimethylpicolinic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE U LCMS Ex. # Structure Chemical Name m/z 89

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-5-fluoro-2-methoxynicotinamide 574.3 (M + H) 90

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-4-methoxypyrimidine- 2-carboxamide 557.3 (M + H) 91

5-cyano-N-(1-(5-(3-cyano- 6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-2-methylbenzamide 564.3 (M + H) 92

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-4-fluorobenzamide 543.2 (M + H) 93

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-4-fluoro-2-methylbenzamide 557.3 (M + H) 94

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-fluoro-6-methylpicolinamide 558.3 (M + H) 95

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-4-oxo-1,4-dihydropyridine-3- carboxamide 542.3 (M + H) 96

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-4-oxo-1,4-dihydropyridine-2- carboxamide 542.3 (M + H) 97

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-1-methyl-2-oxo-1,2- dihydropyridine-3- carboxamide 556.2 (M + H) 98

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-1,6-dimethyl-4-oxo- 1,4-dihydropyridine-2- carboxamide 570.3 (M + H)99

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3-fluoro-6-oxo-1,6- dihydropyridine-2- carboxamide 560.3 (M + H) 100

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-(methoxymethyl)benzamide 569.3 (M + H) 101

2-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide 573.2 (M + H) 102

2-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-6-fluorobenzamide 577.2 (M + H) 103

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-4,6-dimethylpicolinamide 554.3 (M + H) 104

3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide 578.2 (M + H)

Example 105

2-chloro-N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamideA mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 56 mg, 0.11 mmol), HATU (47.5 mg,0.125 mmol), and 2-Chloro-5-fluorobenzoic acid (39.6 mg, 0.23 mmol) inDMSO (1.13 mL, 0.1 M) was treated with DIEA (0.06 mL, 0.125 mmol) andthen stirred for 4h at ambient temperature. The reaction mixture wasconcentrated in vacuo. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was suspended in 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (34.3 mg, 52% yield).MS (apci) m/z=577.2 (M+H).

The compounds in Table V were prepared using a similar method to thatdescribed for the synthesis of Example 105, replacing2-Chloro-5-fluorobenzoic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE V LCMS Ex. # Structure Chemica Name m/z 106

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-5-fluoro-2-methoxybenzamide 573.3 (M + H) 107

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-fluoro-6-methoxypicolinamide 574.2 (M + H)

Example 108

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3,5-difluoro-2-methoxybenzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 52 mg, 0.105 mmol), HATU (44.1 mg,0.116 mmol), 3,5-difluoro-2-methoxybenzoic acid (19.8 mg, 0.105 mmol) inDMSO (1.05 mL, 0.1 M) was treated with DIEA (0.09 mL, 0.527 mmol) andthen stirred for 2h at ambient temperature. The reaction mixture wasdiluted with EtOAc and washed with water. The organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (41.6 mg, 66.8% yield). MS (apci) m/z=591.3 (M+H).

Example 109

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-(hydroxymethyl)benzamide

Prepared using a similar method to that described for the synthesis ofExample 108, replacing 3,5-difluoro-2-methoxybenzoic acid with theappropriate carboxylic acid. The reaction was monitored for completionby LCMS, and reaction duration was adjusted accordingly. The titlecompound was cleanly isolated following chromatographic purificationusing an appropriate gradient eluent (and if necessary converted to thefree base). MS (apci) m/z=555.3 (M+H).

Example 110

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide

Step 1: Preparation of tert-butyl5-((1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 50 mg, 0.10 mmol), HATU (42 mg, 0.11mmol),2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid(56 mg, 0.20 mmol) in DMSO (1.0 mL, 0.1 M) was treated with DIEA (0.09mL, 0.51 mmol) and then stirred for 2 h at ambient temperature. Thereaction mixture was concentrated in vacuo. The reaction mixture wasdiluted with EtOAc and washed with water. The organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(0.5-9% MeOH in DCM with 0.05-0.9% NH₄OH as the gradient eluent) toafford the title compound (63 mg, 91% yield) in sufficient purity forstep 2. MS (apci) m/z=680.4 (M+H)

Step 2: Preparation ofN-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide.Tert-butyl5-((1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(62 mg, 0.091 mmol) in DCM (0.46 mL) was treated with TFA (0.46 mL, 0.68mmol) and stirred at ambient temperature for 15 minutes. The reactionwas concentrated in vacuo and resuspended in 10 mL DCM and passedthrough a Pl-HCO₃ resin to free-base product. Plug was washed with 10 mLDCM. Solution was concentrated in vacuo to afford the title compound (53mg, 100% yield) in sufficient purity for step 3. MS (apci) m/z=580.3(M+H)

Step 3: Preparation ofN-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide.N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide(53 mg, 0.091 mmol) in DMA (0.9 mL, 0.1M) was treated with sodiumtriacetoxyhydroborate (194 mg, 0.914 mmol) followed by formaldehyde (127μL, 0.457 mmol). The reaction was stirred at ambient temperature for 30min. The reaction mixture was diluted with EtOAc and washed with water.The organic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. An additional aqueousextraction was performed using 20 mL 4:1 DCM:IPA, organics were driedwith anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1DCM:IPA. The combined organic extracts were washedwith brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (41.6 mg, 66.8%yield). MS (apci) m/z=594.3 (M+H).

Example 111

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-cyclopropylacetamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 21 mg, 0.05 mmol), HATU (23 mg, 0.06 mmol),Cyclopropylacetic acid (5 mg, 0.05 mmol) in DCM (100 μL) was treatedwith DIEA (35 μL, 0.2 mmol) and then stirred for 18 h at ambienttemperature. The reaction mixture was diluted with DCM and washed withwater. The organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The residuewas purified by silica chromatography (50-100% EtOAc in Hexanes then0-20% MeOH in EtOAc as the gradient eluent) to cleanly provide the titlecompound (17 mg, 67.5% yield) MS (apci) m/z=503.30 (M+H).

The compounds in Table W were prepared using a similar method to thatdescribed for the synthesis of Example 111, replacing cyclopropylaceticacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent (and if necessaryconverted to the free base).

TABLE W LCMS Ex. # Structure Chemical Name m/z 112

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-6-methylpicolinamide 540.30 (M + H) 113

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)nicotinamide526.25 (M + H) 114

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3,3-dimethylbutanamide 519.30 (M + H) 115

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-5-methylpicolinamide 540.30 (M + H)

Example 116

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)propionamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 21.3 mg, 0.051 mmol), HATU (21 mg, 0.055 mmol),propionic acid (3.4 μL, 0.046 mmol) in DCM (92 μL) was treated with DIEA(32 μL, 0.18 mmol) and then stirred for 18 h at ambient temperature. Thereaction mixture was diluted with DCM and washed with water. The organicextracts were washed with brine, then dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was purified by silicachromatography (50-100% EtOAc in Hexanes then 0-20% MeOH in EtOAc as thegradient eluent) to cleanly provide the title compound (17.5 mg, 79.7%yield) MS (apci) m/z=477.25 (M+H).

The compounds in Table X were prepared using a similar method to thatdescribed for the synthesis of Example 116, replacing propionic acidwith the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent (and if necessaryconverted to the free base).

TABLE X LCMS Ex. # Structure Chemical Name m/z 117

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)cyclopropanecarboxamide 489.30 (M + H) 118

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3,3,3-trifluoropropanamide 531.20 (M + H)

Example 119

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-4-methylpicolinamide2,2,2-trifluoroacetate

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 20 mg, 0.048 mmol), HATU (54 mg, 0.14 mmol),4-methylpicolinic acid (6.52 mg, 0.048 mmol) in DCM (238 μL) was treatedwith DIEA (33 μL, 0.19 mmol) and then stirred for 1 h at ambienttemperature. The reaction mixture was filtered to remove solids, thenthe filtrate was concentrated in vacuo. The residue was purified by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt (14.2 mg,55.3% yield). MS (apci) m/z=540.3 (M+H).

The compounds in Table Y were prepared using a similar method to thatdescribed for the synthesis of Example 119, replacing 4-methylpicolinicacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent.

TABLE Y LCMS Ex. # Structure Chemical Name m/z 120

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-methyl-2-phenylpropanamide 2,2,2- trifluoroacetate 567.3 (M + H) 121

2-(4-chlorophenyl)-N-(1- (5-(3-cyano-6-(2-hydroxy- 2-methylpropoxy)pyrazolo [1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4- yl)-2-methylpropanamide2,2,2-trifluoroacetate 601.3 (M + H)

Example 122

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-6-methylnicotinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 20 mg, 0.048 mmol), HATU (54 mg, 0.14 mmol),6-methylnicotinic acid (6.52 mg, 0.048 mmol) in DCM (238 μL) was treatedwith DIEA (33 μL, 0.19 mmol) and then stirred for 4 h at ambienttemperature. The reaction was purified directly by silica chromatography(1-10% MeOH in CHCl₃ with 0.1-1% NH₄OH as the gradient eluent) tocleanly provide the title compound (10 mg, 39% yield) MS (apci)m/z=540.3 (M+H).

The compounds in Table Z were prepared using a similar method to thatdescribed for the synthesis of Example 122, replacing 6-methylnicotinicacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent (and if necessaryconverted to the free base).

TABLE Z LCMS Ex. # Structure Chemical Name m/z 123

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-2-methylnicotinamide 540.3 (M + H) 124

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3-methylpicolinamide 540.3 (M + H) 125

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-2-phenylacetamide 539.3 (M + H) 126

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-methyl-3-phenylbutanamide 581.3 (M + H) 127

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-4-methylnicotinamide 540.3 (M + H) 128

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-5-methylnicotinamide 540.3 (M + H)

Example 129

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-methoxy-2-methylbenzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P46; 50 mg, 0.12 mmol), HATU (54 mg, 0.14 mmol),3-methoxy-2-methylbenzoic acid (24 mg, 0.14 mmol) in DMSO (793 L) wastreated with DIEA (25 μL, 0.14 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The solution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (25 mg, 37% yield).MS (apci) m/z=569.3 (M+H).

The compounds in Table AA were prepared using a similar method to thatdescribed for the synthesis of Example 129, replacing3-methoxy-2-methylbenzoic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE AA MS (apci) Ex. # Structure Chemica Name m/z 130

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-5-methoxy-2-methylbenzamide 569.3 (M + H) 131

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-2,6-dimethylbenzamide 553.3 (M + H)

Example 132

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3,5-difluoropicolinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 50 mg, 0.10 mmol), HATU (59 mg, 0.16mmol), 3,5-difluoropicolinic acid (25 mg, 0.16 mmol) in DMSO (793 μL)was treated with DIEA (73 μL, 0.42 mmol) and then stirred for 18 h atambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The solution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (29.7 mg, 44.5%yield). MS (apci) m/z=562.2 (M+H).

The compounds in Table BB were prepared using a similar method to thatdescribed for the synthesis of Example 132, replacing3,5-difluoropicolinic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE BB LCMS Ex. # Structure Chemical Name m/z 133

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-fluoro-5-methylbenzamide 557.3 (M + H) 134

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-methylisonicotinamide 540.3 (M + H) 135

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-4,6-dimethoxypyrimidine-2- carboxamide 587.3 (M + H) 136

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-4-methylpyrimidine-2- carboxamide 541.3 (M + H) 137

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-4-methylpyrimidine-5- carboxamide 541.3 (M + H) 138

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-6-methyl-4-oxo-1,4- dihydropyridine-2- carboxamide 556.3 (M + H) 139

2-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3,5-difluorobenzamide 595.2 (M + H) 140

5-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2-methylisonicotinamide 561.3 (M + H) 141

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-4,6-dimethylpyrimidine-2- carboxamide 555.3 (M + H) 142

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-3-((dimethylamino)methyl) benzamide 582.3 (M + H)

Example 143

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 50 mg, 0.10 mmol), HATU (90 mg, 0.238mmol), 6-hydroxy-3-methylpicolinic acid (36 mg, 0.238 mmol) in DMSO (793μL) was treated with DIEA (93 μL, 0.535 mmol) and then stirred for 18 hat ambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The solution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (10 mg, 15.1% yield).MS (apci) m/z=556.3 (M+H).

The compounds in Table CC were prepared using a similar method to thatdescribed for the synthesis of Example 143, replacing6-Hydroxy-3-methylpicolinic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE CC LCMS Ex. # Structure Chemical Name m/z 144

2-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)benzamide559.2 (M + H) 145

5-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-4-methylnicotinamide 574.3 (M + H) 146

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4- yl)-2,3,6-trifluorobenzamide 579.3 (M + H)

Example 147

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylisonicotinamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P48; 50 mg, 0.10 mmol), HATU (90 mg, 0.238mmol), 5-Fluoro-2-methylisonicotinic acid (18 mg, 0.12 mmol) in DMSO(793 μL) was treated with DIEA (93 μL, 0.535 mmol) and then stirred for18 h at ambient temperature. The reaction mixture was diluted with EtOAcand washed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The reaction was purified directly by silica chromatography (1-10% MeOHin DCM as the gradient eluent) to cleanly provide the title compound(41.9 mg, 63.2% yield) MS (apci) m/z=558.3 (M+H).

Example 148

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-1,5-dimethyl-1H-pyrazole-4-carboxamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P46; 50 mg, 0.12 mmol), HATU (54 mg, 0.14mmol), 1,5-dimethyl-1H-pyrazole-4-carboxylic acid (25 mg, 0.18 mmol) inDCM (2.4 mL) was treated with DIEA (104 μL, 0.59 mmol) and then stirredfor 16 h at ambient temperature. The reaction mixture was diluted withDCM and washed with saturated NaHCO₃. The organic extracts were driedover anhydrous Na₂SO4(s), filtered and concentrated in vacuo. Thereaction was purified by silica chromatography (1-10% MeOH in EtOAc asthe gradient eluent) to cleanly provide the title compound (41.9 mg,63.2% yield) MS (apci) m/z=543.20 (M+H).

The compounds in Table DD were prepared using a similar method to thatdescribed for the synthesis of Example 148, replacing1,5-dimethyl-1H-pyrazole-4-carboxylic acid with the appropriatecarboxylic acid. Reactions were monitored for completion by LCMS, andreaction durations were adjusted accordingly. Title compounds werecleanly isolated following chromatographic purification using anappropriate gradient eluent (and if necessary converted to the freebase).

TABLE DD LCMS Ex. # Structure Chemical Name m/z 149

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-1-methyl-1H-pyrazole- 4-carboxamide 528.6 (M + H) 150

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-1,3-dimethyl-1H- pyrazole-4-carboxamide 543.2 (M + H)

Example 151

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-methyloxazole-4-carboxamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P46; 50 mg, 0.12 mmol), HATU (54 mg, 0.14mmol), 2-methyloxazole-4-carboxylic acid (18 mg, 0.14 mmol) in DCM (2.4mL) was treated with DIEA (104 μL, 0.59 mmol) and then stirred for 20 hat ambient temperature. The reaction mixture was diluted with DCM (5 mL)and washed with 0.1M NaOH. The organic extracts were dried overanhydrous Na2SO4(s), filtered and concentrated in vacuo. The residue wastriturated with MTBE to cleanly provide the title compound (15 mg, 23.8%yield) MS (apci) m/z=543.20 (M+H).

The compounds in Table EE were prepared using a similar method to thatdescribed for the synthesis of Example 151, replacing2-methyloxazole-4-carboxylic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing the same a basic workup and trituration purification.

TABLE EE LCMS Ex. # Structure Chemical Name m/z 152

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-1-methyl-1H-pyrazole- 3-carboxamide 528.2  (M + H) 153

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-1,4-dimethyl-1H- imidazole-5-carboxamide 543.20 (M + H) 154

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-1-isopropyl-1H- pyrazole-4-carboxamide 557.20 (M + H)

Example 155

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-3-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 30.7 mg, 0.0941 mmol), 3-(azetidin-3-yloxy)pyridine(28.3 mg, 0.188 mmol) and TEA (78.7 μL, 0.564 mmol) in DMA (627 μL) wasstirred overnight at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with water and washed with DCM. The organicextracts were washed with brine and dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo. The residue was purified by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was dissolved in DCM and washed with saturated Na₂CO₃(aq). Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo to cleanlyprovide the title compound (17 mg, 39.6% yield). MS (apci) m/z=457.2(M+H).

The compounds in Table FF were prepared using a similar method to thatdescribed for the synthesis of Example 155, replacing3-(azetidin-3-yloxy)pyridine with the appropriate azetidine nucleophile.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE FF LCMS Ex. # Structure Chemical Name m/z 156

4-(6-(3-(4- cyanophenoxy)azetidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 481.1 (M + H) 157

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- (m-tolyloxy)azetidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 470.2 (M + H)158

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- (2- methoxyethoxy)azetidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 438.2 (M + H)159

4-(6-(3-(2- fluorophenoxy)azetidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 474.1 (M + H) 160

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- ((5-methoxypyridin-3-yl)oxy)azetidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 487.1 (M + H) 161

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- (p-tolyloxy)azetidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 470.2 (M + H)162

4-(6-(3-(3- chlorophenoxy)azetidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 490.1 (M + H)

Example 163

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(4-(trifluoromethyl)phenoxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 36.4 mg, 0.112 mmol),3-(4-(trifluoromethyl)phenoxy)azetidine hydrochloride (70.7 mg, 0.279mmol) and TEA (93.3 μL, 0.669 mmol) in DMA (372 μL) was stirredovernight at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with water and washed with DCM. The organic extractswere washed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was dissolvedin DCM and washed with saturated Na₂CO₃(aq). The combined organicextracts were washed with brine, then dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo to cleanly provide the title compound(15 mg, 25.7% yield). MS (apci) m/z=524.1 (M+H).

Example 164

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((3-methylpyridin-2-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol),2-(azetidin-3-yloxy)-3-methylpyridine dihydrochloride (76.3 mg, 0.322mmol) and TEA (117 μL, 0.858 mmol) in DMA (358 μL) was stirred overnightat 105° C. After cooling to ambient temperature, the reaction mixturewas diluted with DCM and washed with saturated Na₂CO₃(aq). The organicextracts were washed with water. Then the organic extracts were washedwith brine and dried over anhydrous Na₂SO₄(s), filtered and concentratedin vacuo. The residue was suspended in 60:40 ACN:water containing 2%TFA. The solution was purified directly by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO_(3(aq)) and extracted with DCM. The combinedorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (9.4 mg, 18.6% yield). MS (apci) m/z=471.10 (M+H).

The compounds in Table GG were prepared using a similar method to thatdescribed for the synthesis of Example 164, replacing2-(azetidin-3-yloxy)-3-methylpyridine dihydrochloride with theappropriate azetidine nucleophile. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent (and if necessaryconverted to the free base).

TABLE GG LCMS Ex. # Structure Chemical Name m/z 165

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- ((5-methylpyridin-2-yl)oxy)azetidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 471.20 (M + H) 166

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- ((1-methyl-1H-pyrazol-5-yl)oxy)azetidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 460.20 (M + H) 167

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- ((5-methoxypyridin-2-yl)oxy)azetidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 487.20 (M + H) 168

4-(6-(3-(3- fluorophenoxy)azetidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 474.20 (M + H)

Example 169

4-(6-(3-(4-fluorophenoxy)azetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 36.5 mg, 0.112 mmol), 3-(4-fluorophenoxy)azetidinehydrochloride (68.3 mg, 0.336 mmol) and TEA (91.8 μL, 0.671 mmol) in DMA(358 μL) was stirred overnight at 105° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withwater. Then the organic extracts were washed with brine and dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue wassuspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (23.5 mg, 44.4% yield). MS (apci)m/z=474.20 (M+H).

Example 170

4-(6-(3-((5-fluoropyridin-2-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol),2-(azetidin-3-yloxy)-5-fluoropyridine dihydrochloride (51.7 mg, 0.215mmol) and TEA (65.1 μL, 0.644 mmol) in DMA (358 μL) was stirredovernight at 105° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM and washed with water. Then the organicextracts were washed with brine and dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo. The residue was suspended in 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with DCM.The combined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (8.3 mg, 16.3% yield). MS (apci) m/z=475.20 (M+H).

Example 171

4-(6-(3-((5-chloropyridin-2-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol),2-(azetidin-3-yloxy)-5-chloropyridine dihydrochloride (94.7 mg, 0.368mmol) and TEA (117 μL, 0.858 mmol) in DMA (358 μL) was stirred overnightat 105° C. After cooling to ambient temperature, the reaction mixturewas diluted with DCM and washed with water. Then the organic extractswere washed with brine, dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (19.1 mg, 36.3% yield). MS (apci) m/z=491.10 (M+H).

Example 172

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(o-tolyloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol), 3-(2-Methylphenoxy)azetidine(52.2 mg, 0.322 mmol) and TEA (44 μL, 0.322 mmol) in DMA (358 μL) wasstirred overnight at 105° C. After cooling to ambient temperature, thereaction mixture was diluted with DCM and washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The reaction was purifiedby silica chromatography (40-90% EtOAc in Hexanes as the gradienteluent). Impurities remained and product-containing fractions wereconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (21.6 mg, 42.9% yield). MS (apci) m/z=470.20 (M+H).

Example 173

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol), 3-(1-methylethoxy)-azetidinehydrochloride (48.8 mg, 0.322 mmol) and TEA (73 μL, 0.536 mmol) in DMA(358 μL) was stirred overnight at 90° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withwater. The organic extracts were washed with brine and dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue wassuspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (16.8 mg, 37.2% yield). MS (apci)m/z=422.20 (M+H).

The compounds in Table HH were prepared using a similar method to thatdescribed for the synthesis of 173, replacing3-(1-methylethoxy)-azetidine hydrochloride with the appropriateazetidine nucleophile. Reactions were monitored for completion by LCMS,and reaction durations were adjusted accordingly. Title compounds werecleanly isolated following chromatographic purification using anappropriate gradient eluent (and if necessary converted to the freebase).

TABLE HH LCMS Ex. # Structure Chemical Name m/z 174

4-(6-(3-((5-fluoro-6- methoxypyridin-3- yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 505.20 (M + H) 175

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- ((6-methylpyridazin-3-yl)oxy)azetidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 472.20 (M + H)

Example 176

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-methyl-3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 76.1 mg, 0.233 mmol),2-((3-methylazetidin-3-yl)oxy)pyridine (95 mg, 0.579 mmol) and TEA (159μL, 1.17 mmol) in DMA (777 μL) was stirred overnight at 105° C. Aftercooling to ambient temperature, the reaction mixture was diluted withDCM and washed with water. The organic extracts were washed with brineand dried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo.The residue was suspended in 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (33 mg, 30.1% yield).MS (apci) m/z=471.20 (M+H).

Example 177

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 75.8 mg, 0.232 mmol),5-(azetidin-3-yloxy)-2-methoxypyridine (93 mg, 0.516 mmol) and TEA (118μL, 1.16 mmol) in DMA (774 μL) was stirred overnight at 95° C. Aftercooling to ambient temperature, the reaction mixture was diluted withDCM and washed with water. The organic extracts were washed with brineand dried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo.The residue was suspended in 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (65.6 mg, 58% yield).MS (apci) m/z=487.15 (M+H).

Example 178

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((5-methoxypyrazin-2-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 32.2 mg, 0.0987 mmol),2-(azetidin-3-yloxy)-5-methoxypyrazine (41.7 mg, 0.230 mmol) and TEA(67.5 μL, 0.493 mmol) in DMA (329 μL) was stirred overnight at 95° C.After cooling to ambient temperature, the reaction mixture was dilutedwith DCM and washed with water. The organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was suspended in 60:40 ACN:water containing 2% TFA.The solution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (14.8 mg, 30.8%yield). MS (apci) m/z=488.20 (M+H).

Example 179

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridazin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 32.2 mg, 0.0987 mmol),3-(azetidin-3-yloxy)-6-methoxypyridazine (51 mg, 0.281 mmol) and TEA(67.5 μL, 0.493 mmol) in DMA (329 μL) was stirred overnight at 95° C.After cooling to ambient temperature, the reaction mixture was dilutedwith DCM and washed with water. The organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was suspended in 60:40 ACN:water containing 2% TFA.The solution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (28.6 mg, 59.5%yield). MS (apci) m/z=488.20 (M+H).

Example 180

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((2-methoxypyrimidin-5-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 30.0 mg, 0.0919 mmol),5-(azetidin-3-yloxy)-2-methoxypyrimidine (56 mg, 0.309 mmol) and TEA(101 μL, 0.735 mmol) in DMA (306 μL) was stirred overnight at 95° C.After cooling to ambient temperature, the reaction mixture was dilutedwith DCM and washed with water. The organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was suspended in 60:40 ACN:water containing 2% TFA.The solution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (14.9 mg, 33.2%yield). MS (apci) m/z=488.20 (M+H).

Example 181

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(3-(trifluoromethyl)phenoxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 31.9 mg, 0.0978 mmol),3-[3-(trifluoromethyl)phenoxy]azetidine hydrochloride (74.4 mg, 0.293mmol) and TEA (93.6 μL, 0.684 mmol) in DMA (326 μL) was stirredovernight at 105° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM and washed with saturated NaHCO_(3(aq)).The organic extracts were washed with water. Then the organic extractswere washed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (36.6 mg, 71.5% yield). MS (apci) m/z=524.10 (M+H).

The compounds in Table II were prepared using a similar method to thatdescribed for the synthesis of Example 181, replacing3-[3-(trifluoromethyl)phenoxy]azetidine hydrochloride with theappropriate azetidine nucleophile. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification.

TABLE II LCMS Ex. # Structure Chemical Name m/z 182

6-(2-hydroxy-2- methylpropoxy)-4-(6-(3- ((6- (trifluoromethyl)pyridin-2-yl)oxy)azetidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 525.10 (M + H) 183

4-(6-(3-(4- chlorophenoxy)azetidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 490.10 (M + H) 184

4-(6-(3-(2,4- difluorophenoxy)azetidin- 1-yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 492.15(M + H) 185

4-(6-(3-(2,6- difluorophenoxy)azetidin- 1-yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 492.10(M + H) 186

4-(6-(3-(3,4- difluorophenoxy)azetidin- 1-yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 492.10(M + H) 187

4-(6-(3-(3,5- difluorophenoxy)azetidin- 1-yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 492.15(M + H) 188

4-(6-(3-((5-chloro-6- methoxypyridin-3- yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 521.10 (M + H) 189

4-(6-(3-((5-fluoropyridin- 3-yl)oxy)azetidin-1- yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 475.10(M + H) 190

4-(6-(3- (benzyloxy)azetidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 470.20 (M + H) 191

4-(6-(3-((4- fluorophenyl)amino)azetidin- 1-yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 473.20(M + H)

Example 192

4-(6-(3-((6-(difluoromethoxy)pyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 30.7 mg, 0.0941 mmol),5-(azetidin-3-yloxy)-2-(difluoromethoxy)pyridine (55 mg, 0.254 mmol) andTEA (64.3 μL, 0.470 mmol) in DMA (314 μL) was stirred overnight at 95°C. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc and washed with water. Then the organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (39.9 mg, 81.2% yield). MS (apci) m/z=523.20 (M+H).

Example 193

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((4-methylpyridin-2-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25.5 mg, 0.0781 mmol),2-(azetidin-3-yloxy)-4-methylpyridine (50 mg, 0.304 mmol) and TEA (74.8μL, 0.547 mmol) in DMA (391 μL) was stirred overnight at 95° C. Aftercooling to ambient temperature, the reaction mixture was diluted withwater and extracted with EtOAc. The organic extracts were washed withwater. Then the organic extracts were washed with brine and dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue wassuspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (19.3 mg, 52.5% yield). MS (apci)m/z=471.3 (M+H).

Example 194

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((4-methoxypyridin-2-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 28 mg, 0.0858 mmol),2-(azetidin-3-yloxy)-4-methoxypyridine (15.5 mg, 0.858 mmol) and TEA(82.1 μL, 0.601 mmol) in DMA (286 μL) was stirred overnight at 95° C.After cooling to ambient temperature, the reaction mixture was dilutedwith water and extracted with EtOAc. The organic extracts were washedwith water. Then the organic extracts were washed with brine and driedover anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (16.9 mg, 40.5% yield). MS (apci)m/z=487.20 (M+H).

Example 195

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-ylmethoxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25 mg, 0.077 mmol),2-((azetidin-3-yloxy)methyl)pyridine (17 mg, 0.10 mmol) and TEA (73 μL,0.54 mmol) in DMA (260 μL) was stirred overnight at 95° C. After coolingto ambient temperature, the reaction mixture was diluted with water andextracted with EtOAc. The organic extracts were washed with water. Thenthe organic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was suspendedin 60:40 ACN:water containing 2% TFA. The solution was purified directlyby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted withDCM. The combined organic extracts were washed with brine, then driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (6.6 mg, 18% yield). MS (apci) m/z=471.20(M+H).

Example 196

6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((pyridin-2-yloxy)methyl)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 26 mg, 0.0797 mmol), 2-(azetidin-3-ylmethoxy)pyridine(73.5 mg, 0.448 mmol) and TEA (76.3 μL, 0.558 mmol) in DMA (266 μL) wasstirred overnight at 95° C. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted with EtOAc. Theorganic extracts were washed with water. Then the organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (16.6 mg, 44.3% yield). MS (apci) m/z=471.20 (M+H).

Example 197

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylazetidin-3-yl)-5-fluoro-2-methylbenzamide

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylazetidin-3-yl)carbamate.A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 753 mg, 2.307 mmol), tert-butyl(3-methylazetidin-3-yl)carbamate hydrochloride (770.9 mg, 3.461 mmol)and DIEA (1.809 mL, 10.38 mmol) in DMSO (4.615 mL) was stirred overnightat 90° C. After cooling to ambient temperature, the reaction mixture wasdiluted with water and extracted with EtOAc. The organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(1-10% MeOH in DCM as the gradient eluent) to afford the title compound(1.089 g, 95.81% yield) in sufficient purity for step 2. MS (apci)m/z=493.3 (M+H).

Step 2: Preparation of4-(6-(3-amino-3-methylazetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylazetidin-3-yl)carbamate(1.089 g, 2.211 mmol) in DCM (5.527 mL) was treated with TFA (10 mL, 130mmol). After stirring for 1 h at ambient temperature the mixture wasconcentrated in vacuo and the residue diluted with EtOAc and washed withsaturated NaHCO_(3(aq)).The organic extracts were washed with brine anddried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo tocleanly provide the title compound (800 mg, 92.2% yield) in sufficientpurity for step 3. MS (apci) m/z=393.2 (M+H).

Step 3: Preparation ofN-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylazetidin-3-yl)-5-fluoro-2-methylbenzamide.A mixture of4-(6-(3-amino-3-methylazetidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(54 mg, 0.138 mmol), HATU (57.5 mg, 0.151 mmol),5-Fluoro-2-methylbenzoic acid (42.4 mg, 0.275 mmol) in DMSO (1.38 mL)was treated with DIEA (120 μL, 0.688 mmol) and then stirred overnight atambient temperature. The reaction mixture was diluted with EtOAc andwashed with water. The organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was purified by silica chromatography (0.5-10% MeOH in DCMwith 0.05-1% NH₄OH as the gradient eluent) to cleanly provide the titlecompound (48.2 mg, 66.3% yield) MS (apci) m/z=529.2 (M+H)

Example 198

(R)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpyrrolidine-3-carboxamideStep 1: Preparation of tert-butyl(R)-3-(phenylcarbamoyl)pyrrolidine-1-carboxylate

A mixture of (R)-1-N-Boc-beta-proline (504.1 mg, 2.34 mmol), HATU (1.069g, 2.810 mmol), and Aniline (239.9 mg, 2.576 mmol) in DCM (25 mL) wastreated with DIEA (816 μL, 4.684 mmol) and then stirred 60 hours atambient temperature. The reaction mixture concentrated in vacuo. Theresidue was purified by silica chromatography (10-60% EtOAc in Hexanesas the gradient eluent) to afford the title compound (assumedtheoretical yield, 679 mg, 2.34 mmol) in sufficient purity for step 2.MS (apci) m/z=191.10 (M−Boc).

Step 2: Preparation of (R)-N-phenylpyrrolidine-3-carboxamide

Tert-butyl (R)-3-(phenylcarbamoyl)pyrrolidine-1-carboxylate (assumed 679mg, 2.34 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 16 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (218.9 mg, 49.13% yield over two steps) insufficient purity for step 3. MS (apci) m/z=191.10 (M+H).

Step 3: Preparation of(R)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpyrrolidine-3-carboxamide.A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 33.4 mg, 0.102 mmol,(R)-N-phenylpyrrolidine-3-carboxamide (58.4 mg, 0.307 mmol) and TEA(69.4 μL, 0.512 mmol) in DMA (512 μL) was stirred overnight at 80° C.After cooling to ambient temperature, the reaction mixture was dilutedwith EtOAc and washed with water. The organic extracts were washed withbrine and the organic extracts were concentrated in vacuo. The residuewas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (36.8 mg, 72.4% yield). MS (apci) m/z=497.2(M+H).

Example 199

(S)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpyrrolidine-3-carboxamideStep 1: Preparation of tert-butyl(S)-3-(phenylcarbamoyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl (S)-3-(phenylcarbamoyl)pyrrolidine-1-carboxylate (518.6 mg, 2.409 mmol), HATU (1.008g, 2.891 mmol), and aniline (269.3 mg, 2.891 mmol) in DCM (25 mL) wastreated with DIEA (816 μL, 4.684 mmol) and then stirred 60 hours atambient temperature. The reaction mixture concentrated in vacuo. Theresidue was purified by silica chromatography (10-60% EtOAc in Hexanesas the gradient eluent) to afford the title compound (assume theoreticalyield, 699 mg, 2.409 mmol) in sufficient purity for step 2. MS (apci)m/z=191.10 (M−Boc).

Step 2: Preparation of (S)-N-phenylpyrrolidine-3-carboxamide

Tert-butyl (S)-3-(phenylcarbamoyl)pyrrolidine-1-carboxylate (assumed 699mg, 2.409 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 16 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (458.4 mg, 98% yield over two steps) insufficient purity for step 3. MS (apci) m/z=191.10 (M+H).

Step 3: Preparation of(S)-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpyrrolidine-3-carboxamide.A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 28 mg, 0.086 mmol),(S)-N-phenylpyrrolidine-3-carboxamide (49 mg, 0.257 mmol) and TEA (58μL, 0.429 mmol) in DMA (572 μL) was stirred overnight at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc and washed with water. The organic extracts were washed with brineand the organic extracts were concentrated in vacuo. The residue waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (16.7 mg, 39% yield). MS (apci) m/z=497.2(M+H).

Example 200

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4′-methyl-[1,4′-bipiperidin]-1′-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 50 mg, 0.153 mmol), 4′-Methyl-[1,4′]bipiperidinyldihydrochloride (54.7 mg, 0.215 mmol) and DIEA (133 μL, 0.766 mmol) inDMSO (306 μL) was sparged with argon and stirred overnight at 90° C.After cooling to ambient temperature, the reaction mixture was dilutedwith EtOAc and washed with water. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with EtOAc. The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated invacuo to afford the title compound (27 mg, 36% yield). MS (apci)m/z=489.3 (M+H).

Example 201

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 394 mg, 1.208 mmol,(S)-2-(pyrrolidin-3-yloxy)-pyridine dihydrochloride (1.146 g, 4.833mmol) and TEA (1.639 mL, 12.08 mmol) in DMA (12 mL) was stirred 16 h at90° C. After cooling to ambient temperature, the reaction mixture wasdiluted with water and extracted with EtOAc. The organic extracts werewashed with water. Then the organic extracts were washed with brine anddried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was purified directly by C18 reverse phase chromatography (5-95%ACN in water with 0.1% TFA as the gradient eluent) to afford the titlecompound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with 4:1 DCM:IPA. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (400 mg, 70% yield).MS (apci) m/z=471.2 (M+H). ¹H NMR (400 MHz, DMSO) δ 8.65-8.64 (d, 1H),8.56 (s, 1H), 8.31-8.30 (dd, 1H), 8.22-8.20 (m, 1H), 7.76-7.69 (m, 2H),7.26-7.25 (d, 1H), 7.01-6.98 (m, 1H), 6.85-6.83 (m, 1H), 6.61-6.59 (d,1H), 5.69-5.67 (m, 1H), 4.69 (s, 1H), 3.86-3.81 (m, 3H), 3.70-3.65 (m,2H), 3.60-3.53 (m, 1H), 2.42-2.22 (m, 2H), 1.22 (s, 6H)

Example 202

(R)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25 mg, 0.077 mmol) in DMA (100 μL) was treated withTEA (27 μL, 0.192 mmol) and (R)-2-(pyrrolidin-3-yloxy)pyridinehydrochloride (15.4 mg, 0.077 mmol) and was stirred overnight at 110° C.After cooling to ambient temperature, the reaction mixture was dilutedwith water (10 mL) and extracted with DCM (3×10 mL) using a phaseseparator frit. The organic extracts were concentrated in vacuo. Theresidue was purified directly by C18 reverse phase chromatography (0-60%ACN in water as the gradient eluent) to cleanly provide the titlecompound (16 mg, 44% yield). MS (apci) m/z=471.2 (M+H).

Example 203

(S)-4-(6-(3-(4-fluorophenoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 31.6 mg, 0.097 mmol) in DMA (1 mL) was treated with(S)-3-(4-fluorophenoxy)pyrrolidine hydrochloride (22.1 mg, 0.102 mmol)followed by TEA (65.7 μL, 0.484 mmol) and was stirred overnight at 90°C. Additional (S)-3-(4-fluorophenoxy)pyrrolidine hydrochloride (8.8 mg,0.48 mmol) was added to the reaction and reaction continued to stir foran additional 16 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted with EtOAc. Theorganic extracts were washed with water. Then the organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(5-50% Acetone in DCM as the gradient eluent). An impurity remained soproduct-containing fractions were concentrated in vacuo. The residue wasrepurified by C18 reverse phase chromatography (5-95% ACN in water with0.1% TFA as the gradient eluent) to afford the title compound as the TFAsalt. The TFA salt was treated with saturated NaHCO_(3(aq)) andextracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (9.8 mg, 20.8% yield). MS (apci) m/z=488.2(M+H).

Example 204

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyrazin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-(pyrazin-2-yloxy)pyrrolidine-1-carboxylate

To a solution of tert-butyl(S)-3-(phenylcarbamoyl)pyrrolidine-1-carboxylate (264.5 mg, 1.413 mmol)in DMF (7.1 mL) was added 2-chloropyrazine (192.2 mg, 1.695 mmol)followed by sodium hydride (60% w/w, 113 mg, 2.825 mmol) and then thereaction mixture was stirred for 16 hours at 80° C. After cooling toambient temperature, the reaction mixture was diluted with water andextracted with EtOAc. The organic extracts were washed with water. Thenthe organic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was purifiedby silica chromatography (5-60% EtOAc in Hexanes as the gradient eluent)to afford the title compound (assume theoretical yield, 374.9 mg, 1.413mmol) in sufficient purity for step 2. ¹H NMR (400 MHz, DMSO-d6) δ 8.31(s, 1H), 8.22 (s, 2H), 5.49 (s, 1H), 3.64-3.57 (m, 1H), 3.48-3.31 (m,3H), 2.23-2.04 (m, 2H), 1.40-1.39 (d, 9H).

Step 2: Preparation of (S)-2-(pyrrolidin-3-yloxy)pyrazine

To a solution of tert-butyl(S)-3-(pyrazin-2-yloxy)pyrrolidine-1-carboxylate (assumed 374.9 mg,1.413 mmol) in 3 mL DCM was treated with TFA (3 mL, 39 mmol). Thereaction mixture was stirred for 0.5 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (72.1 mg, 31% yield over two steps) insufficient purity for step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),8.21 (s, 2H), 5.46-5.42 (m, 1H), 3.25-3.21 (m, 1H), 3.09-2.95 (m, 3H),2.17-2.08 (m, 1H), 1.96-1.89 (m, 1H).

Step 3: Preparation of(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyrazin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 30.8 mg, 0.094 mmol) in DMA (2 mL) was added TEA (64μL, 0.472 mmol) followed by (S)-2-(pyrrolidin-3-yloxy)pyrazine (71.7 mg,0.434 mmol). The reaction mixture was stirred overnight at 90° C. Aftercooling to ambient temperature, the reaction was purified directly byC18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent). An impurity remained and product-containingfractions were concentrated in vacuo. The residue was repurified bysilica chromatography (5-95% Acetone in DCM as the gradient eluent) toafford the title compound (36.2 mg, 81% yield). MS (apci) m/z=472.2(M+H).

Example 205

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((6-methoxypyridin-3-yl)oxy)pyrrolidine-1-carboxylate

To a solution of tert-butyl (R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (Intermediate R14; 208.7 mg,0.787 mmol) in DMF (8 mL) was added 5-hydroxy-2-methoxylpyridine (118.1mg, 0.944 mmol) followed by potassium carbonate (217.4 mg, 1.573 mmol)and then the reaction mixture was stirred for 16 hours at 90° C. Aftercooling to ambient temperature, the reaction mixture was diluted withwater and extracted with EtOAc. The organic extracts were washed withwater. Then the organic extracts were washed with brine and dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (5-75% Acetone in DCM as the gradienteluent) to afford the title compound (assume theoretical yield, 231 mg,0.787 mmol) in sufficient purity for step 2. MS (apci) m/z=295.1 (M+H).

Step 2: Preparation of (S)-2-methoxy-5-(pyrrolidin-3-yloxy)pyridine

To a solution of tert-butyl(S)-3-((6-methoxypyridin-3-yl)oxy)pyrrolidine-1-carboxylate (assumed 231mg, 0.787 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 15 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (54.6 mg, 36% yield over two steps) insufficient purity for step 3. MS (apci) m/z=195.1 (M+H).

Step 3: Preparation of(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 60.8 mg, 0.186 mmol) in DMA (2 mL) was added TEA (126μL, 0.932 mmol) followed by (S)-2-methoxy-5-(pyrrolidin-3-yloxy)pyridine(54.3 mg, 0.279 mmol). The reaction mixture was stirred overnight at 90°C. After cooling to ambient temperature, the reaction was purified byC18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (39.5 mg, 42% yield). MS (apci) m/z=501.2 (M+H).

Example 206

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((5-fluoropyridin-2-yl)oxy)pyrrolidine-1-carboxylate

To a solution of tert-butyl (R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (Intermediate R14; 200.8 mg,0.757 mmol) in DMF (8 mL) was added 5-fluoro-2-hydroxypyridine (102.7mg, 0.908 mmol) followed by potassium carbonate (209.2 mg, 1.514 mmol)and then the reaction mixture was stirred for 60 hours at 90° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc washed with water. Then the organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was purified by silica chromatography (5-75% Acetonein DCM as the gradient eluent) to afford the title compound (assumetheoretical yield, 213.5 mg, 0.757 mmol) in sufficient purity for step2. MS (apci) m/z=183.1 (M−Boc).

Step 2: Preparation of (S)-5-fluoro-2-(pyrrolidin-3-yloxy)pyridine

To a solution tert-butyl(S)-3-((5-fluoropyridin-2-yl)oxy)pyrrolidine-1-carboxylate (assumed213.5 mg, 0.75 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 15 min at ambient temperature, andthen concentrated in vacuo. The crude residue was diluted with 4:1 DCM:IPA and washed with saturated NaHCO_(3(aq)). The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (57.2 mg, 41% yield over two steps) insufficient purity for step 3. MS (apci) m/z=183.1 (M+H).

Step 3: Preparation of(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 30.3 mg, 0.093 mmol) and(S)-5-fluoro-2-(pyrrolidin-3-yloxy)pyridine (55.8 mg, 0.31 mmol) in DMA(2 mL) was added TEA (63 μL, 0.464 mmol). The reaction mixture wasstirred 16 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The reaction was purifiedby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (29.6 mg, 65% yield). MS (apci) m/z=489.2 (M+H).

Example 207

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridin-2-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((6-methoxypyridin-2-yl)oxy)pyrrolidine-1-carboxylate

To a mixture of (S)-1-Boc-3-hydroxypyrrolidine(112.5 mg, 0.601 mmol) and2-Chloro-6-methoxypyridine (86 μL, 0.721 mmol) in DMF (6 mL) was addedsodium hydride (60% w/w, 48.1 mg, 1.20 mmol) and then the reactionmixture was stirred for 16 hours at 80° C. Additional sodium hydride(60% w/w, 48.1 mg, 1.20 mmol) was added and the reaction mixture wasstirred for an additional 16 hours at 80° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc and washed withwater. Then the organic extracts were washed with brine and dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (5-95% EtOAc in Hexanes as thegradient eluent) to afford the title compound as crude product that wasdirectly used in the next step, assuming quantitative yield. MS (apci)m/z=195.1 (M−Boc).

Step 2: Preparation of (S)-2-methoxy-6-(pyrrolidin-3-yloxy)pyridine

To a solution of tert-butyl(S)-3-((6-methoxypyridin-2-yl)oxy)pyrrolidine-1-carboxylate (assumed176.8 mg, 0.601 mmol) in 2 mL DCM was treated with TFA (2 mL). Thereaction mixture was stirred for 15 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (81.6 mg, 70% yield over two steps) insufficient purity for step 3. MS (apci) m/z=195.1 (M+H).

Step 3: Preparation of(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridin-2-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 57.2 mg, 0.175 mmol) and(S)-2-methoxy-6-(pyrrolidin-3-yloxy)pyridine (71.5 mg, 0.368 mmol) inDMA (3 mL) was added TEA (64 μL, 0.472 mmol). The reaction mixture wasstirred overnight at 80° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The reaction was purifiedby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (56.6 mg, 65% yield). MS (apci) m/z=501.2 (M+H).

Example 208

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methylpyridin-2-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((6-methylpyridin-2-yl)oxy)pyrrolidine-1-carboxylate

To a mixture of (S)-1-Boc-3-hydroxypyrrolidine (112.5 mg, 0.601 mmol)and 2-chloro-6-methylpyridine (74 μL, 0.669 mmol) in DMF (6 mL) wasadded sodium hydride (60% w/w, 44.6 mg, 1.11 mmol) and then the reactionmixture was stirred for 16 hours at 80° C. Additional sodium hydride(60% w/w, 44.6 mg, 1.11 mmol) was added and the reaction mixture wasstirred for an additional 16 hours at 80° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc and washed withwater. Then the organic extracts were washed with brine and dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (5-95% EtOAc in Hexanes as thegradient eluent) to afford the title compound (assume theoretical yield,155 mg, 0.557 mmol) in sufficient purity for step 2. MS (apci) m/z=279.1(M+H).

Step 2: Preparation of (S)-2-methyl-6-(pyrrolidin-3-yloxy)pyridine

To a solution of tert-butyl(S)-3-((6-methylpyridin-2-yl)oxy)pyrrolidine-1-carboxylate (assumed 155mg, 0.557 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 15 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (81.6 mg, 70% yield over two steps) insufficient purity for step 3. MS (apci) m/z=179.1(M+H).

Step 3: Preparation of(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methylpyridin-2-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 53.3 mg, 0.163 mmol) and(S)-2-methyl-6-(pyrrolidin-3-yloxy)pyridine (69.9 mg, 0.392 mmol) in DMA(2 mL) was added TEA (111 μL, 0.817 mmol). The reaction mixture wasstirred overnight at 80° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was purifiedby silica chromatography 1-30% MeOH in EtOAc with 0.1-2% NH₄OH as thegradient eluent) to cleanly provide the title compound (60.8 mg, 76.8%yield) MS (apci) m/z=485.2 (M+H)

Example 209

(S)-4-(6-(3-((5-fluoropyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((5-fluoropyridin-3-yl)oxy)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (Intermediate R14;301.5 mg, 1.136 mmol) and 5-fluoropyridin-3-ol (154.2 mg, 1.364 mmol) inDMF (11 mL) was added potassium carbonate (314.1 mg, 2.273 mmol) andthen the reaction mixture was stirred for 16 hours at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc washed with water. Then the organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was purified by silica chromatography (5-95% EtOAc inHexanes as the gradient eluent) to afford the title compound (assumetheoretical yield, 320.7 mg, 1.136 mmol) in sufficient purity for step2. MS (apci) m/z=183.1 (M−Boc).

Step 2: Preparation of (S)-3-fluoro-5-(pyrrolidin-3-yloxy)pyridine

To a solution tert-butyl(S)-3-((5-fluoropyridin-3-yl)oxy)pyrrolidine-1-carboxylate (assumed320.7 mg, 1.136 mmol) in 2.5 mL DCM was treated with TFA (2.5 mL, 32.7mmol). The reaction mixture was stirred for 15 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasdiluted with 4:1 DCM: IPA and washed with saturated NaHCO_(3(aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (57.2 mg, 41% yieldover two steps) in sufficient purity for step 3. MS (apci) m/z=183.1(M+H).

Step 3: Preparation of(S)-4-(6-(3-((5-fluoropyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 32.7 mg, 0.10 mmol) and(S)-3-fluoro-5-(pyrrolidin-3-yloxy)pyridine (48.4 mg, 0.266 mmol) in DMA(2 mL) was added TEA (68 μL, 0.501 mmol). The reaction mixture wasstirred 16 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was purifiedby silica chromatography 1-30% MeOH in EtOAc with 0.1-2% NH₄OH as thegradient eluent) to cleanly provide the title compound (23 mg, 47%yield) MS (apci) m/z=489.2 (M+H)

Example 210

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((5-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((5-methoxypyridin-3-yl)oxy)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (Intermediate R14;301.6 mg, 1.137 mmol) and 5-methoxypyridin-3-ol (170.7 mg, 1.364 mmol)in DMF (11 mL) was added potassium carbonate (314 mg, 2.273 mmol) andthen the reaction mixture was stirred for 16 hours at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc washed with water. Then the organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was purified by silica chromatography (5-95% EtOAc inHexanes as the gradient eluent) to afford the title compound (assumetheoretical yield, 334.7 mg, 1.137 mmol) in sufficient purity for step2. MS (apci) m/z=239.1 (M- t-Bu fragment).

Step 2: Preparation of (S)-3-methoxy-5-(pyrrolidin-3-yloxy)pyridine

To a solution of tert-butyl(S)-3-((5-methoxypyridin-3-yl)oxy)pyrrolidine-1-carboxylate (assumed334.7 mg, 1.137 mmol) in 2.5 mL DCM was treated with TFA (2.5 mL, 32.7mmol). The reaction mixture was stirred for 15 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasdiluted with 4:1 DCM: IPA and washed with saturated NaHCO_(3(aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (59.4 mg, 26.9% yieldover two steps) in sufficient purity for step 3. MS (apci) m/z=195.1(M+H).

Step 3: Preparation of((S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((5-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 30 mg, 0.092 mmol) and(S)-3-methoxy-5-(pyrrolidin-3-yloxy)pyridine (59.4 mg, 0.306 mmol) inDMA (2 mL) was added TEA (62 μL, 0.46 mmol). The reaction mixture wasstirred 16 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was purifiedby silica chromatography 1-30% MeOH in EtOAc with 0.1-2% NH₄OH as thegradient eluent) to cleanly provide the title compound (32.6 mg, 71%yield) MS (apci) m/z=501.2 (M+H)

Example 211

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((2-methoxypyrimidin-5-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((2-methoxypyrimidin-5-yl)oxy)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (Intermediate R14;374.0 mg, 1.410 mmol) and 2-methoxypyrimidine-5-ol (213.3 mg, 1.692mmol) in DMF (14 mL) was added potassium carbonate (390 mg, 2.819 mmol)and then the reaction mixture was stirred for 60 hours at 80° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc washed with water. Then the organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was purified by silica chromatography (5-95% EtOAc inHexanes as the gradient eluent) to afford the title compound (assumetheoretical yield, 416.4 mg, 1.410 mmol) in sufficient purity for step2. MS (apci) m/z=196.1 (M−Boc).

Step 2: Preparation of and(S)-2-methoxy-5-(pyrrolidin-3-yloxy)pyrimidine

To a solution of tert-butyl(S)-3-((2-methoxypyrimidin-5-yl)oxy)pyrrolidine-1-carboxylate (assumed416.4 mg, 1.410 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 15 min at ambient temperature, andthen concentrated in vacuo. The crude residue was diluted with 4:1 DCM:IPA and washed with saturated NaHCO_(3(aq)). The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (61.7 mg, 20% yield over two steps) insufficient purity for step 3. MS (apci) m/z=196.1 (M+H).

Step 3: Preparation of(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((2-methoxypyrimidin-5-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 31.7 mg, 0.097 mmol) and(S)-2-methoxy-5-(pyrrolidin-3-yloxy)pyrimidine (60.7 mg, 0.311 mmol) inDMA (2 mL) was added TEA (79 μL, 0.58 mmol). The reaction mixture wasstirred 16 h at 80° C. The reaction mixture was stirred at 80° C. for 16hours. The reaction was heated to 100° C. for 60 hours. The reaction washeated to 150° C. for 2 hours in a microwave reactor. The reaction washeated to 150° C. for 8 hours in a microwave reactor. After cooling toambient temperature, the reaction mixture was diluted with EtOAc washedwith water. Then the organic extracts were washed with brine and driedover anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Thereaction was purified by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (16.6 mg, 34% yield). MS (apci) m/z=502.3(M+H).

Example 212

(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridazin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((6-methoxypyridazin-3-yl)oxy)pyrrolidine-1-carboxylate

To a mixture of (S)-1-Boc-3-hydroxypyrrolidine (83.9 mg, 0.448 mmol)3-Chloro-6-methoxypyridazine (77.7 mg, 0.538 mmol) in DMF (4.5 mL) wasadded sodium hydride (60% w/w, 35.8 mg, 0.896 mmol) and then thereaction mixture was stirred for 60 hours at 80° C. Additional sodiumhydride (60% w/w, 35.8 mg, 0.896 mmol) was added and the reactionmixture was stirred for an additional 16 hours at 80° C. After coolingto ambient temperature, the reaction mixture was diluted with EtOAc andwashed with water. Then the organic extracts were washed with brine anddried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was purified by silica chromatography (5-95% EtOAc in Hexanes asthe gradient eluent) to afford the title compound (assume theoreticalyield, 132 mg, 0.448 mmol) in sufficient purity for step 2. MS (apci)m/z=295.1 (M+H).

Step 2: Preparation of (S)-3-methoxy-6-(pyrrolidin-3-yloxy)pyridazine

To a solution of tert-butyl(S)-3-((6-methoxypyridazin-3-yl)oxy)pyrrolidine-1-carboxylate (assumed132 mg, 0.448 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 15 min at ambient temperature, andthen concentrated in vacuo. The crude residue was diluted with 4:1 DCM:IPA and washed with saturated NaHCO_(3(aq)). The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (17.6 mg, 20.1% yield over two steps) insufficient purity for step 3.

Step 3: Preparation of(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-((6-methoxypyridazin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 22.4 mg, 0.069 mmol) and(S)-3-methoxy-6-(pyrrolidin-3-yloxy)pyridazine (17.4 mg, 0.892 mmol) inDMA (3 mL) was added TEA (46 μL, 0.343 mmol). The reaction mixture wasstirred 16 h at 80° C. The reaction mixture was stirred for 60 h at 100°C. The reaction mixture was then stirred for 2 h at 150° C. in amicrowave reactor. The reaction was heated for an additional 8 h at 150°C. in a microwave reactor. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The reaction was purifiedby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO3(aq) and extracted with 4:1DCM:IPA. The combined organic extracts were dried over anhydrousNa2SO4(s), filtered and concentrated in vacuo to afford the titlecompound (6.3 mg, 18.3% yield). MS (apci) m/z=502.2 (M+H).

Example 213

(S)-4-(6-(3-((5-chloro-6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-3-((5-chloro-6-methoxypyridin-3-yl)oxy)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (Intermediate R14;602.2 mg, 2.27 mmol) and 3-Chloro-5-hydroxy-2-methoxypyridine (301.8 mg,1.891 mmol) in DMF (22 mL) was added potassium carbonate (522.8 mg,3.783 mmol) and then the reaction mixture was stirred for 60 hours at80° C. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc washed with water. Then the organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(5-95% EtOAc in Hexanes as the gradient eluent) to afford the titlecompound (assume theoretical yield, 621.7 mg, 1.891 mmol) in sufficientpurity for step 2. MS (apci) m/z=229.1 (M−Boc).

Step 2: Preparation of(S)-3-chloro-2-methoxy-5-(pyrrolidin-3-yloxy)pyridine

To a solution tert-butyl(S)-3-((5-chloro-6-methoxypyridin-3-yl)oxy)pyrrolidine-1-carboxylate(assumed 621.7 mg, 1.891 mmol) in 2 mL DCM was treated with TFA (2 mL,26 mmol). The reaction mixture was stirred for 15 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasdiluted with 4:1 DCM: IPA and washed with saturated NaHCO_(3(aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (140.6 mg, 32.5%yield over two steps) in sufficient purity for step 3. MS (apci)m/z=229.10 (M+H).

Step 3: Preparation of(S)-4-(6-(3-((5-chloro-6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 26.4 mg, 0.081 mmol) and(S)-3-chloro-2-methoxy-5-(pyrrolidin-3-yloxy)pyridine (64.7 mg, 0.283mmol) in DMA (1 mL) was added TEA (66 μL, 0.49 mmol). The reactionmixture was stirred 16 h at 80° C. After cooling to ambient temperature,the reaction mixture was diluted with EtOAc washed with water. Then theorganic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The reaction was purifiedby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (27.2 mg, 63% yield). MS (apci) m/z=535.2 (M+H).

Example 214

6-(2-hydroxy-2-methylpropoxy)-4-(6-((trans)-3-methyl-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(trans)-3-methyl-4-(pyridin-2-yloxy)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(trans)-3-hydroxy-4-methylpyrrolidine-1-carboxylate (303.8 mg, 1.509mmol) and 2-fluoropyridine (259 μL, 3.019 mmol) in DMA (7.5 mL) wasadded sodium hydride (60% w/w, 120.7 mg, 3.019 mmol). The reactionmixture was stirred for 16 h at 80° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc and washed withwater. Then the organic extracts were washed with brine and dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue waspurified by silica chromatography (5-50% EtOAc in hexanes as thegradient eluent) to afford the title compound (assume theoretical yield,420 mg, 1.509 mmol) in sufficient purity for step 2. MS (apci) m/z=279.1(M+H).

Step 2: Preparation of 2-(((trans)-4-methylpyrrolidin-3-yl)oxy)pyridine

To a solution of tert-butyl(trans)-3-hydroxy-4-methylpyrrolidine-1-carboxylate (assumed 420 mg,1.509 mmol) in 3 mL DCM was treated with TFA (3 mL, 39.2 mmol). Thereaction mixture was stirred for 15 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (178.6 mg, 66% yield over two steps) insufficient purity for step 3. MS (apci) m/z=179.1 (M+H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-((trans)-3-methyl-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol) and2-(((trans)-4-methylpyrrolidin-3-yl)oxy)pyridine (76.5 mg, 0.428 mmol)in DMA (1.1 mL) was added TEA (145 μL, 1.07 mmol). The reaction mixturewas stirred 16 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted with EtOAc. Theorganic extracts were washed with water. Then the organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The reaction was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO₃(aq) and extracted with 4:1 DCM:IPA. The combinedorganic extracts were dried over anhydrous Na2SO4(s), filtered andconcentrated in vacuo to afford the title compound (38.2 mg, 73.5%yield). MS (apci) m/z=485.2 (M+H).

Example 215

(S)-4-(6-(3-((5-fluoro-6-methoxypyridin-2-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of 3,6-difluoro-2-methoxypyridine

To a solution of 2,3,6-Trifluoropyridine (1.00 mL, 11.27 mmol) in MeOH(11 mL) was added sodium methoxide (30% solution in MeOH, 2.5 mL), 13.5mmol). The reaction solution was stirred for 2 h at 70° C. After coolingto ambient temperature, the reaction mixture was diluted with EtOAc andwashed with water. Then the organic extracts were washed with brine anddried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo toafford the title compound (257 mg, 16% yield) in sufficient purity forstep 2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.90-7.84 (m, 1H), 6.75-6.72 (m,1H), 3.92 (s, 3H).

Step 2: Preparation of tert-butyl(S)-3-((5-fluoro-6-methoxypyridin-2-yl)oxy)pyrrolidine-1-carboxylate

A solution of (S)-1-Boc-3-hydroxypyrrolidine (255 mg, 1.362 mmol) in13.6 mL DMF was treated with 3,6-difluoro-2-methoxypyridine (256.9 mg,1.77 mmol) followed by sodium hydride (60% w/w, 163.4 mg, 4.086 mmol).The reaction mixture was stirred for 16 h at 80° C. After cooling toambient temperature, the reaction mixture was diluted with water andextracted with EtOAc. The organic extracts were washed with water. Thenthe organic extracts were washed with brine and dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was purifiedby silica chromatography (5-40% EtOAc in Hexanes as the gradient eluent)to afford the title compound (assume theoretical yield, 425 mg, 1.362mmol) in sufficient purity for step 3. MS (apci) m/z=213.1 (M−Boc).

Step 3: Preparation of(S)-3-fluoro-2-methoxy-6-(pyrrolidin-3-yloxy)pyridine

To a solution of tert-butyl(S)-3-((5-fluoro-6-methoxypyridin-2-yl)oxy)pyrrolidine-1-carboxylate(assumed 425 mg, 1.362 mmol) in 3 mL DCM was treated with TFA (3 mL, 39mmol). The reaction mixture was stirred for 30 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasdiluted with 4:1 DCM: IPA and washed with saturated NaHCO_(3(aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (222.2 mg, 77% yieldover two steps) in sufficient purity for step 4. MS (apci) m/z=213.1(M+H).

Step 4: Preparation of(S)-4-(6-(3-((5-fluoro-6-methoxypyridin-2-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35.2 mg, 0.108 mmol) in DMA (1.1 mL) was added(S)-3-fluoro-2-methoxy-6-(pyrrolidin-3-yloxy)pyridine (91.6 mg, 0.431mmol) followed by TEA (145 μL, 1.07 mmol). The reaction mixture wasstirred 16 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted with EtOAc. Theorganic extracts were washed with water. Then the organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The reaction was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO3(aq) and extracted with 4:1 DCM:IPA. The combinedorganic extracts were dried over anhydrous Na2SO4(s), filtered andconcentrated in vacuo to afford the title compound (44.8 mg, 80.1%yield). MS (apci) m/z=519.2 (M+H).

Example 216

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 29 mg, 0.09 mmol) and1-(4-Piperidinyl)-2-pyrrolidinone (30 mg, 0.18 mmol) in DMA (2 mL) wasadded TEA (61 μL, 0.45 mmol). The reaction mixture was stirred 16 h at80° C. After cooling to ambient temperature, additional and1-(4-piperidinyl)-2-pyrrolidinone (30 mg, 0.18 mmol) was added andreaction was stirred 16 h at 80° C. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc and washed withwater and brine. The organic extracts were concentrated in vacuo. Theresidue was purified by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (14.1 mg, 33% yield). MS (apci) m/z=475.2(M+H).

Example 217

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpiperidine-4-carboxamideStep 1: Preparation of tert-butyl4-(phenylcarbamoyl)piperidine-1-carboxylate

A mixture of Boc-Inp-OH (253 mg, 1.10 mmol), HATU (504 mg, 1.33 mmol),and aniline (111 μL, 1.22 mmol) in DCM (11 mL) was treated with DIEA(385 μL, 2.21 mmol) and then stirred for 12 h at ambient temperature.The reaction mixture was concentrated in vacuo and the residue waspurified by silica chromatography (5-95% EtOAc in Hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 338 mg) in sufficient purity for step 2. MS (apci) m/z=205.1(M−Boc).

Step 2: Preparation of N-phenylpiperidine-4-carboxamide

To a solution of tert-butyl 4-(phenylcarbamoyl)piperidine-1-carboxylate(assumed 338 mg, 1.104 mmol) in 2 mL DCM was treated with TFA (2 mL, 26mmol). The reaction mixture was stirred for 30 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasdiluted with 4:1 DCM: IPA and washed with saturated NaHCO_(3(aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (67 mg, 30% yieldover two steps) in sufficient purity for step 3. MS (apci) m/z=205.1(M+H).

Step 3: Preparation of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpiperidine-4-carboxamide.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 28 mg, 0.09 mmol) andN-phenylpiperidine-4-carboxamide (66 mg, 0.32 mmol) in DMA (0.5 mL) wasadded TEA (59 μL, 0.43 mmol). The reaction mixture was stirred 16 h at80° C. After cooling to ambient temperature, additional TEA (59 μL, 0.43mmol) was added and reaction was stirred 16 h at 90° C. After cooling toambient temperature, the reaction mixture was diluted with EtOAc andwashed with water and brine. The organic extracts were concentrated invacuo. The residue was purified by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with 4:1 DCM:IPA. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (21 mg, 47% yield).MS (apci) m/z=511.2 (M+H).

Example 218

N-benzyl-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxamideStep 1: Preparation of tert-butyl4-(benzylcarbamoyl)piperidine-1-carboxylate

A mixture of Boc-Inp-OH (250 mg, 1.09 mmol), HATU (498 mg, 1.31 mmol),and benzylamine (131 μL, 1.20 mmol) in DCM (11 mL) was treated with DIEA(380 μL, 2.18 mmol) and then stirred for 60 h at ambient temperature.The reaction mixture was concentrated in vacuo and the residue waspurified by silica chromatography (5-95% EtOAc in Hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 347 mg) in sufficient purity for step 2. MS (apci) m/z=219.1(M−Boc).

Step 2: Preparation of N-benzylpiperidine-4-carboxamide

To a solution of tert-butyl 4-(benzylcarbamoyl)piperidine-1-carboxylate(assumed 347 mg, 1.09 mmol) in 2 mL DCM was treated with TFA (2 mL, 26mmol). The reaction mixture was stirred for 30 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasdiluted with 4:1 DCM: IPA and washed with saturated NaHCO_(3(aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (33 mg, 14% yieldover two steps) in sufficient purity for step 3. MS (apci) m/z=219.2(M+H).

Step 3: Preparation ofN-benzyl-1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxamide.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 19 mg, 0.06 mmol) andN-benzylpiperidine-4-carboxamide (33 mg, 0.15 mmol) in DMA (0.3 mL) wasadded TEA (40 μL, 0.29 mmol). The reaction mixture was stirred 16 h at80° C. After cooling to ambient temperature, additional TEA (40 μL, 0.29mmol) was added and reaction was stirred 16 h at 90° C. After cooling toambient temperature, the reaction mixture was diluted with EtOAc andwashed with water and brine. The organic extracts were concentrated invacuo. The residue was purified by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with 4:1 DCM:IPA. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (19 mg, 63% yield).MS (apci) m/z=525.2 (M+H).

Example 219

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-ylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-(pyridin-2-ylthio)piperidine-1-carboxylate

To a solution of tert-butyl 4-mercaptopiperidine-1-carboxylate (205 mg,0.94 mmol) and 2-iodopyridine (263 mg, 1.28 mmol) in DMF (3.8 mL) wasadded potassium carbonate (521 mg, 3.8 mmol). The reaction mixture wasstirred 16 h at 70° C. The reaction was heated 16 h at 90° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc and washed with water and brine. The organic extracts were driedover anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was purified using silica chromatography (0-50% EtOAc in Hexanesas the gradient eluent) to afford the title compound (106.2 mg, 361mmol) in sufficient purity for step 2. MS (apci) m/z=295.2 (M+H).

Step 2: Preparation of tert-butyl4-(pyridin-2-ylsulfonyl)piperidine-1-carboxylate

Tert-butyl 4-(pyridin-2-ylthio)piperidine-1-carboxylate (106 mg, 0.36mmol) and 3-chlorobenzoperoxoic acid (187 mg, 1.08 mmol) were combinedin DCM (3.6 mL) at 0° C. The reaction mixture was warmed to ambienttemperature and stirred for 16h. The reaction mixture was concentratedin vacuo. The residue was diluted with 4:1 DCM:IPA and was washed withsaturated NaHCO_(3(aq)). The organic extracts were concentrated invacuo. The residue was purified by silica chromatography (0-95% EtOAc inHexanes as the gradient eluent) to afford the title compound (assumedtheoretical yield, 118 mg) in sufficient purity for step 3. MS (apci)m/z=227.1 (M-Boc).

Step 3: Preparation of 2-(piperidin-4-ylsulfonyl)pyridine

To a solution of tert-butyl4-(pyridin-2-ylsulfonyl)piperidine-1-carboxylate (assumed 118 mg, 0.36mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). The reactionmixture was stirred for 15 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts wereconcentrated in vacuo to afford the title compound (47 mg, 57% yieldover two steps) in sufficient purity for step 4. MS (apci) m/z=227.1(M+H).

Step 4: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-ylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 27 mg, 0.08 mmol) and2-(piperidin-4-ylsulfonyl)pyridine (57 mg, 0.25 mmol) in DMA (0.5 mL)was added TEA (57 μL, 0.42 mmol). The reaction mixture was stirred 60 hat 80° C. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc and washed with water and brine. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(0-100% EtOAc in Hexanes as the gradient eluent) to afford the titlecompound (20 mg, 46% yield). MS (apci) m/z=533.2 (M+H).

Example 220

4-(6-(4-((cyclopropylmethyl)sulfonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((cyclopropylmethyl)thio)piperidine-1-carboxylate

To a solution of tert-butyl 4-mercaptopiperidine-1-carboxylate (222 mg,1.02 mmol) and (Bromomethyl)cyclopropane (184 mg, 1.36 mmol) in DMF (4mL) was added potassium carbonate (566 mg, 4.09 mmol). The reactionmixture was stirred 60 h at 70° C. After cooling to ambient temperature,the reaction mixture was diluted with EtOAc and washed with water andbrine. The organic extracts were dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo. The residue was purified usingsilica chromatography (5-95% EtOAc in Hexanes as the gradient eluent) toafford the title compound (256 mg, 92% yield) in sufficient purity forthe next step. ¹H NMR (400 MHz, DMSO-d₆) δ 3.81-3.77 (m, 2H), 2.92-2.86(m, 2H), 2.48-2.47 (d, 2H), 1.89-1.85 (m, 2H), 1.38 (s, 9H), 1.33-1.23(m, 2H), 0.93-0.89 (m, 1H), 0.51-0.47 (m, 2H), 0.19-0.16 (m, 2H).

Step 2: Preparation of tert-butyl4-((cyclopropylmethyl)sulfonyl)piperidine-1-carboxylate

Tert-butyl 4-((cyclopropylmethyl)thio)piperidine-1-carboxylate (256 mg,0.94 mmol) and 3-chlorobenzoperoxoic acid (187 mg, 1.08 mmol) werecombined in DCM (9.5 mL) at 0° C. The reaction mixture was warmed toambient temperature and stirred for 16 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with 4:1 DCM:IPA and waswashed with saturated NaHCO_(3(aq)). The organic extracts wereconcentrated in vacuo. The residue was purified by silica chromatography(0-95% EtOAc in Hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 286 mg) in sufficient purity forstep 3. MS (apci) m/z=204.1 (M−Boc).

Step 3: Preparation of 4-((cyclopropylmethyl)sulfonyl)piperidine

To a solution of tert-butyl4-((cyclopropylmethyl)sulfonyl)piperidine-1-carboxylate (assumed 286 mg,0.94 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 15 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts wereconcentrated in vacuo to afford the title compound (60 mg, 31% yieldover two steps) in sufficient purity for step 4. MS (apci) m/z=204.1(M+H).

Step 4: Preparation of4-(6-(4-((cyclopropylmethyl)sulfonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[,5-a]pyridine-3-carbonitrile(Intermediate P42; 28.1 mg, 0.08 mmol) and of4-((cyclopropylmethyl)sulfonyl)piperidine (53 mg, 0.26 mmol) in DMA (0.5mL) was added TEA (44 μL, 0.43 mmol). The reaction mixture was stirred60 h at 80° C. After cooling to ambient temperature, the reactionmixture was diluted with EtOAc and washed with water and brine. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was purified by silicachromatography (0-100% EtOAc in Hexanes as the gradient eluent).Fractions containing the product were concentrated in vacuo. Residue waspurified by silica chromatography (0-95% EtOAc in Hexanes as thegradient eluent) and product-containing fractions were concentrated invacuo. Residue was purified by C18 reverse phase chromatography (5-95%ACN in water with 0.1% TFA as the gradient eluent) to afford the titlecompound as the TFA salt. The TFA salt was treated with saturatedNaHCO₃(aq) and extracted with 4:1 DCM:IPA. The combined organic extractswere dried over anhydrous Na2SO4(s), filtered and concentrated in vacuoto afford the title compound (21 mg, 48% yield). MS (apci) m/z=510.2(M+H).

Example 221

4-(6-(4-(benzylsulfonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl 4-(benzylthio)piperidine-1-carboxylate

To a solution of tert-butyl 4-mercaptopiperidine-1-carboxylate (211 mg,0.97 mmol) and Benzyl bromide (200 mg, 1.17 mmol) in DMF (3.9 mL) wasadded potassium carbonate (537 mg, 3.89 mmol). The reaction mixture wasstirred 60 h at 70° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc and washed with water and brine.The organic extracts were concentrated in vacuo. The residue waspurified using silica chromatography (1-50% EtOAc in Hexanes as thegradient eluent) to afford the title compound (290 mg, 97% yield) insufficient purity for step 2. MS (apci) m/z=208.1 (M−Boc).

Step 2: Preparation of tert-butyl4-(benzylsulfonyl)piperidine-1-carboxylate

Tert-butyl 4-(benzylthio)piperidine-1-carboxylate (290 mg, 0.94 mmol)and 3-chlorobenzoperoxoic acid (489 mg, 1.08 mmol) were combined in DCM(9.5 mL) at 0° C. The reaction mixture was warmed to ambient temperatureand stirred for 16 h. The reaction mixture was concentrated in vacuo.The residue was diluted with 4:1 DCM:IPA and was washed with saturatedNaHCO_(3(aq)). The organic extracts were concentrated in vacuo. Theresidue was purified by silica chromatography (0-95% EtOAc in Hexanes asthe gradient eluent) to afford the title compound (assumed theoreticalyield, 320 mg) in sufficient purity for step 3. MS (apci) m/z=240.1(M−Boc).

Step 3: Preparation of 4-(benzylsulfonyl)piperidine

To a solution of tert-butyl 4-(benzylsulfonyl)piperidine-1-carboxylate(assumed 320 mg, 0.94 mmol) in 2 mL DCM was treated with TFA (2 mL, 26mmol). The reaction mixture was stirred for 15 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasdiluted with 4:1 DCM: IPA and washed with saturated NaHCO_(3(aq)). Theorganic extracts were concentrated in vacuo to afford the title compound(138 mg, 61% yield over two steps) in sufficient purity for step 4. MS(apci) m/z=240.1 (M+H).

Step 4: Preparation of4-(6-(4-(benzylsulfonyl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 24 mg, 0.074 mmol) and of4-(benzylsulfonyl)piperidine (53 mg, 0.22 mmol) in DMA (0.5 mL) wasadded TEA (50 μL, 0.37 mmol). The reaction mixture was stirred 76 h at80° C. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc and washed with water and brine. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(0-100% EtOAc in Hexanes as the gradient eluent). Fractions containingthe product were concentrated in vacuo. Residue was purified by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (23 mg, 57% yield). MS (apci) m/z=546.2 (M+H).

Example 222

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-phenylpiperidine-4-carboxamideStep 1: Preparation of tert-butyl4-ethyl-4-(phenylcarbamoyl)piperidine-1-carboxylate

A mixture of 1-(tert-butoxycarbonyl)-4-ethylpiperidine-4-carboxylic acid(270 mg, 1.05 mmol), HATU (478 mg, 1.26 mmol), and aniline (105 μL, 1.15mmol) in DMF (3.9 mL) was treated with DIEA (365 μL, 2.1 mmol) and thenstirred for 60 h at 60° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc and washed with water and brine.The combined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was purified by silicachromatography (0-100% EtOAc in Hexanes as the gradient eluent) toafford the title compound (assumed theoretical yield, 348 mg) insufficient purity for step 2. MS (apci) m/z=233.2 (M−Boc).

Step 2: Preparation of 4-ethyl-N-phenylpiperidine-4-carboxamide

To a solution of tert-butyl4-ethyl-4-(phenylcarbamoyl)piperidine-1-carboxylate (assumed 348 mg,1.05 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (162 mg, 67% yield over two steps) insufficient purity for step 3. MS (apci) m/z=233.1 (M+H).

Step 3: Preparation of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-phenylpiperidine-4-carboxamide.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 20 mg, 0.06 mmol) and4-ethyl-N-phenylpiperidine-4-carboxamide (42 mg, 0.18 mmol) in DMA (0.24mL) was added TEA (41 μL, 0.30 mmol). The reaction mixture was stirred16 h at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with EtOAc and washed with water and brine. Theorganic extracts were concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The residue wasrepurified using silica chromatography (0-100% EtOAc in Hexanes) toafford the title compound (27 mg, 82% yield). MS (apci) m/z=539.3 (M+H).

Example 223

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-ylsulfinyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-ylthio)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P54, 27 mg, 0.054 mmol) and 3-chloroperoxybenzoic acid (93mg, 0.54 mmol) were combined in EtOH (270 μL). The reaction was stirredovernight at ambient temperature. The reaction mixture was concentratedin vacuo. The residue was suspended in 60:40 ACN:water containing 2%TFA. The solution was purified directly by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO_(3(aq)) and extracted with DCM. The combinedorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (13.9 mg, 50% yield). MS (apci) m/z=517.2 (M+H).

Example 224

(R)-N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)benzamide

A mixture of(R)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)(Intermediate P49; 40 mg, 0.098 mmol), HATU(75 mg, 0.20 mmol), and benzoic acid (24 mg, 0.20 mmol) in ACN (600 μL)was treated with DIEA (86 μL, 0.49 mmol) and then stirred for 12 h atambient temperature. The reaction mixture was diluted with 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with EtOAc.The combined organic extracts were washed with brine, then dried overanhydrous MgSO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (15 mg, 46% yield). MS (apci) m/z=511.3 (M+H).

The compounds in Table JJ were prepared using a similar method to thatdescribed for the synthesis of Example 224, replacing benzoic acid withthe appropriate carboxylic acid. Reactions were monitored for completionby LCMS, and reaction durations were adjusted accordingly. Titlecompounds were cleanly isolated following chromatographic purificationusing an appropriate gradient eluent (and if necessary converted to thefree base).

TABLE JJ LCMS Ex. # Structure Chemical Name m/z 225

(R)-N-(1-(5-(3-cyano-6- (2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-3- methylpyrrolidin-3-yl)-2-phenylacetamide 525.3 (M + H) 226

(R)-N-(1-(5-(3-cyano-6- (2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-3- methylpyrrolidin-3-yl)-2,3-difluorobenzamide 547.3 (M + H) 227

(R)-N-(1-(5-(3-cyano-6- (2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-3- methylpyrrolidin-3-yl)-2,6-difluorobenzamide 547.3 (M + H) 228

(R)-N-(1-(5-(3-cyano-6- (2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-3- methylpyrrolidin-3-yl)-5- fluoro-2-methylbenzamide 543.3 (M + H) 229

(R)-3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridin-4- yl)pyridin-2-yl)-3-methylpyrrolidin-3- yl)picolinamide 546.3 (M + H) 230

(R)-N-(1-(5-(3-cyano-6- (2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-3- methylpyrrolidin-3-yl)cyclopropanecarboxamide 475.3 (M + H)

Example 231

(S)-N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)benzamide

A mixture of(S)-4-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P50; 30 mg, 0.047 mmol), HATU(56 mg, 0.15 mmol), and benzoic acid (18 mg, 0.15 mmol) in ACN (600 μL)was treated with DIEA (64 μL, 0.37 mmol) and then stirred for 12 h atambient temperature. The reaction mixture was diluted with 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with EtOAc.The combined organic extracts were washed with brine, then dried overanhydrous MgSO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (12 mg, 51% yield). MS (apci) m/z=511.3 (M+H).

The compounds in Table KK were prepared using a similar method to thatdescribed for the synthesis of Example 231, replacing benzoic acid withthe appropriate carboxylic acid. Reactions were monitored for completionby LCMS, and reaction durations were adjusted accordingly. Titlecompounds were cleanly isolated following chromatographic purificationusing an appropriate gradient eluent (and if necessary converted to thefree base).

TABLE KK LCMS Ex. # Structure Chemical Name m/z 232

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin-3-yl)-2-phenylacetamide 525.3 (M + H) 233

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin- 3-yl)-2,3-difluorobenzamide 547.3 (M + H) 234

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin- 3-yl)-2,6-difluorobenzamide 547.2 (M + H) 235

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin- 3-yl)-5-fluoro-2-methylbenzamide 543.3 (M + H) 236

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin-3-yl)-3-fluoropicolinamide 530.2 (M + H) 237

(S)-3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin- 3-yl)picolinamide 546.2 (M + H) 238

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin- 3-yl)cyclopropanecarboxamide 475.3 (M + H) 239

(S)-2-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-3-methylpyrrolidin- 3-yl)benzamide 545.2 (M + H) 240

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin-3-yl)-2-fluorobenzamide 529.3 (M + H) 241

(S)-N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3-methylpyrrolidin-3-yl)-3-fluorobenzamide 529.2 (M + H)

Example 242

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)benzamide

A mixture of4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P51; 40 mg, 0.064 mmol), HATU(78 mg, 0.20 mmol), and benzoic acid (25 mg, 0.20 mmol) in ACN (600 μL)was treated with DIEA (89 μL, 0.51 mmol) and then stirred for 12 h atambient temperature. The reaction mixture was diluted with 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with EtOAc.The combined organic extracts were washed with brine, then dried overanhydrous MgSO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (15 mg, 47% yield). MS (apci) m/z=497.2 (M+H).

The compounds in Table LL were prepared using a similar method to thatdescribed for the synthesis of Example 242, replacing benzoic acid withthe appropriate carboxylic acid. Reactions were monitored for completionby LCMS, and reaction durations were adjusted accordingly. Titlecompounds were cleanly isolated following chromatographic purificationusing an appropriate gradient eluent (and if necessary converted to thefree base).

TABLE LL LCMS Ex. # Structure Chemical Name m/z 243

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)pyrrolidin-3-yl)-2,3- difluorobenzamide533.2 (M + H) 244

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)pyrrolidin-3-yl)-2,6- difluorobenzamide533.2 (M + H) 245

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)pyrrolidin-3-yl)-3- fluoropicolinamide516.3 (M + H) 246

3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)pyrrolidin-3- yl)picolinamide 532.2 (M + H)

Example 247

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyrimidin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 40 mg, 0.123 mmol) in DMA (1.2 mL) was added2-(piperidin-4-yloxy)pyrimidine (242 mg, 0.135 mmol) followed by TEA(33.5 μL, 0.245 mmol). The reaction mixture was sparged with argon andstirred overnight at 90° C. Then additional2-(piperidin-4-yloxy)pyrimidine (242 mg, 0.135 mmol) and TEA (33.5 μL,0.245 mmol) and the reaction was stirred for 8 h at 110° C. and then thereaction temperature was lowered to 90° C. where it was stirred at for60 h. After cooling to ambient temperature, the reaction mixture wasdiluted with water and extracted with DCM. The organic extracts werewashed with water. Then the organic extracts were washed with brine anddried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Thereaction was purified by silica chromatography (40-99% EtOAc in hexanesas the gradient eluent) to afford the title compound (20.8 mg, 35%yield). MS (apci) m/z=486.2 (M+H).

Example 248

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyrazin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25 mg, 0.077 mmol) in DMA (38 mL) was added2-(piperidin-4-yloxy)pyrazine (13.7 mg, 0.077 mmol) followed by TEA (21μL, 0.153 mmol). The reaction mixture was sparged with argon and stirredfor 60 h at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM the organic extracts were washed withsaturated NaHCO_(3(aq)) and then water. Then the organic extracts werewashed with brine and dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was resuspended in 1 mL DCM and waspurified by silica chromatography (40-99% EtOAc in hexanes as thegradient eluent) to afford the title compound (12.3 mg, 33.1% yield). MS(apci) m/z=486.2 (M+H).

Example 249

4-(6-(4-((5-chloropyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 51.1 mg, 0.157 mmol) in DMA (78 mL) was added5-chloro-2-(piperidin-4-yloxy)pyridine (40 mg, 0.188 mmol) followed byTEA (43 μL, 0.313 mmol). The reaction mixture was stirred for 48 h at90° C. After cooling to ambient temperature, the reaction mixture wasdiluted with DCM the organic extracts were washed with saturatedNaHCO_(3(aq)) and then water. Then the organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The reaction was purified by silica chromatography (40-75% EtOAcin hexanes as the gradient eluent) to afford the title compound (16.1mg, 20% yield). MS (apci) m/z=519.2 (M+H).

Example 250

4-(6-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-chloro-3-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (135 mg,0.67 mmol) in DMF (2.2 mL) was added sodium hydride (60% w/w, 113 mg,2.825 mmol). The mixture stirred at ambient temperature for 30 minutesand then 5-chloro-2,3-difluoropyridine (100 mg, 0.67 mmol) was added.The reaction mixture was stirred for 60 h at 60° C. After cooling toambient temperature, the reaction mixture was diluted with DCM andwashed with saturated NaHCO_(3(aq)) and then water. Then the organicextracts were washed with brine and dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo to afford the title compound (assumetheoretical yield, 222 mg, 0.671 mmol) in sufficient purity for step 2.MS (apci) m/z=213.1 (M−Boc).

Step 2: Preparation of 5-chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine

To a solution of tert-butyl4-((5-chloro-3-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate (assumed222 mg, 0.671 mmol) in 3.4 mL DCM was treated with TFA (3.4 mL, 43.6mmol). The reaction mixture was stirred for 16 h at ambient temperature,and then concentrated in vacuo. The crude residue was resuspended in DCM(1 mL). The solution was purified by silica chromatography 1-10% MeOH inDCM with 0.1-1% NH₄OH as the gradient eluent) to provide the titlecompound (56 mg, 36% yield) in sufficient purity for step 3. MS (apci)m/z=231.1 (M+H).

Step 3: Preparation of4-(6-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25 mg, 0.77 mmol) and5-chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine (35 mg, 0.153 mmol) inDMA (0.4 mL) was added TEA (52 μL, 0.383 mmol). The reaction mixture wasstirred overnight at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with DCM and washed with saturatedNaHCO_(3(aq)) and then water. Then the organic extracts were washed withbrine and dried over anhydrous Na₂SO₄(s), filtered and concentrated invacuo. The residue was purified by silica chromatography (25-99% EtOAcin hexanes as the gradient eluent) to afford the title compound (8.2 mg,20% yield). MS (apci) m/z=357.1 (M+H).

Example 251

4-(6-(4-((5-chloropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-chloropyridin-3-yl)oxy)piperidine-1-carboxylate

A solution of 5-Chloro-3-pyridinol (1.018 g, 0.786 mmol) and tert-butyl4-hydroxypiperidine-1-carboxylate (1.582 mg, 0.786 mmol) in THF wastreated with PPh₃ (227 mg, 0.864 mmol), then sparged with Ar_((g)) for 5min. While stirring at ambient temperature, the mixture was treatedslowly with DIAD (186 μL, 0.959 mmol). The resulting reaction mixturewas stirred for 5 h at 70° C. and then allowed to cool to ambienttemperature. The reaction was diluted with DCM and washed with saturatedNa₂CO_(3(aq)), water and brine. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (246 mg, assumed quantitative yield). MS(apci) m/z=213.1 (M−Boc).

Step 2: Preparation of 3-chloro-5-(piperidin-4-yloxy)pyridineDihydrochloride

To a solution of tert-butyl4-((5-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (264 mg, 0.844mmol) in 4.2 mL DCM was treated with TFA (4.2 mL, 54.5 mmol). Thereaction mixture was stirred for 16 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in MeOH andtreated with then treated with 4 N HCl in dioxanes (5 mL). The solutionwas stirred at ambient temperature and concentrated in vacuo to providethe title compound as a dihydrochloride salt, which was used in the nextstep without further purifications. MS (apci) m/z=213.1 (M+H).

Step 3: Preparation of4-(6-(4-((5-chloropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 40 mg, 0.123 mmol) and3-chloro-5-(piperidin-4-yloxy)pyridine dihydrochloride (35 mg, 0.123mmol) in DMA (0.6 mL) was added TEA (84 μL, 0.613 mmol). The reactionmixture was stirred overnight at 105° C. The reaction was maintained at90° C. for 60 h. After cooling to ambient temperature, the reactionmixture was diluted with DCM and washed with water. Then the organicextracts were washed with brine and dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo. The residue was suspended in 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with DCM.The combined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (8.1 mg, 13% yield). MS (apci) m/z=519.20 (M+H).

Example 252

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((5-methoxypyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-methoxypyridin-2-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (158 mg,0.787 mmol) in DMF (2 mL) was added sodium hydride (60% w/w, 38 mg,0.944 mmol). The reaction was stirred for 10 min at ambient temperature.Then 2-fluoro-5-methoxypyridine (100 mg, 0.787 mmol) was added andreaction stirred overnight at 60° C. The reaction was heated to 70° C.for an additional overnight. The reaction was cooled to ambienttemperature and additional of tert-butyl4-hydroxypiperidine-1-carboxylate (316 mg, 1.574 mmol) and sodiumhydride (60% w/w, 76 mg, 1.888 mmol) was added and reaction was stirredfor 60 h at 70° C. The reaction was cooled to ambient temperature anddiluted with DCM and washed water and brine. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (243 mg, assumedquantitative yield). MS (apci) m/z=253.1 (M−Bu^(t)).

Step 2: Preparation of 5-methoxy-2-(piperidin-4-yloxy)pyridineDihydrochloride

To a solution of tert-butyl4-((5-methoxypyridin-2-yl)oxy)piperidine-1-carboxylate (assumed 243 mg,0.786 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in MeOH andtreated with then treated with 4 N HCl in dioxanes (4 mL). The solutionwas stirred at ambient temperature and concentrated in vacuo to providethe title compound as a dihydrochloride salt (221 mg, 100% yield), whichwas used in the next step without further purifications.

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((5-methoxypyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25 mg, 0.077 mmol) and5-methoxy-2-(piperidin-4-yloxy)pyridine dihydrochloride (43 mg, 0.153mmol) in DMA (0.4 mL) was added TEA (52 μL, 0.383 mmol). The reactionmixture was stirred overnight at 105° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withsaturated NaHCO_(3(aq)), water, and brine. The organic extracts weredried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (4.3 mg, 11% yield). MS (apci)m/z=515.30 (M+H). ¹H-NMR (CDCl₃, 400 MHz) δ 8.34 (m, 1H), 8.20 (s, 1H),8.14 (d, 1H), 7.81 (d, 1H), 7.69-7.72 (m, 1H), 7.20-7.24 (m, 1H), 7.14(m, 1H), 6.81 (d, 1H), 6.68 (m, 1H), 5.20-5.26 (m, 1H), 4.03-4.08 (m,2H), 3.86 (s, 2H), 3.82 (s, 3H), 3.50-3.56 (m, 2H), 2.09-2.14 (m, 2H),2.04 (s, 1H), 1.82-1.89 (m, 2H), 1.40 (s, 6H).

Example 253

4-(6-(4-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (175 mg,0.869 mmol) in DMF (2.9 mL) was added sodium hydride (60% w/w, 41.7 mg,1.043 mmol). The reaction was stirred for 10 min at ambient temperature.2,5-Difluoropyridine (100 mg, 0.869 mmol) was added and reaction stirredovernight at 60° C. The reaction was heated to 70° C. for an additionalovernight. The reaction was cooled to ambient temperature and additionalof tert-butyl 4-hydroxypiperidine-1-carboxylate (316 mg, 1.574 mmol) andsodium hydride (60% w/w, 76 mg, 1.888 mmol) was added and reaction wasstirred for 4 h at 70° C. The reaction was cooled to ambient temperatureand diluted with DCM and washed water and brine. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (257.5 mg, assumedquantitative yield). MS (apci) m/z=197.10 (M−Boc).

Step 2: Preparation of 5-methoxy-2-(piperidin-4-yloxy)pyridineDihydrochloride

To a solution of tert-butyl4-((5-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate (assumed 257.5 mg,0.869 mmol) in 2 mL DCM was treated with 4 N HCl in dioxanes (4 mL). Thesolution was stirred at ambient temperature for 15 min and concentratedin vacuo to provide the title compound as a dihydrochloride salt (202mg, 100% yield) in sufficient purity for step 3 MS (apci) m/z=197.10(M+H).

Step 3: Preparation of4-(6-(4-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol) and5-methoxy-2-(piperidin-4-yloxy)pyridine dihydrochloride (87 mg, 0.322mmol) in DMA (0.4 mL) was added TEA (117 μL, 0.858 mmol). The reactionmixture was stirred overnight at 105° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withwater and brine. The organic extracts were dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was suspendedin 60:40 ACN:water containing 2% TFA. The solution was purified directlyby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted withDCM. The combined organic extracts were washed with brine, then driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (7.7 mg, 14% yield). MS (apci) m/z=503.20(M+H).

Example 254

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.107 mmol) and2-(piperidin-4-yloxy)-5-(trifluoromethyl)pyridine dihydrochloride (79mg, 0.322 mmol) in DMA (0.4 mL) was added TEA (117 μL, 0.858 mmol). Thereaction mixture was stirred overnight at 105° C. After cooling toambient temperature, the reaction mixture was diluted with DCM andwashed with water and brine. The organic extracts were dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue wassuspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (14.6 mg, 25% yield). MS (apci)m/z=553.20 (M+H).

Example 255

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-methyl-4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-methyl-4-(pyridin-2-yloxy)piperidine-1-carboxylate

To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(266 mg, 1.24 mmol) in DMF (2.6 mL) was added sodium hydride (60% w/w,91 mg, 2.27 mmol). The reaction was stirred for 5 min at ambienttemperature. Then 2-Fluoropyridine (100 mg, 1.03 mmol) was added andreaction stirred overnight at 70° C. The reaction was cooled to ambienttemperature and diluted with DCM and washed with saturatedNaHCO_(3(aq)), water, and brine. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was purified by silica chromatography (5-50% EtOAc inhexanes as the gradient eluent) to afford the title compound (assumedquantitative yield, 301 mg) in sufficient purity for step 2. MS (apci)m/z=293.3 (M+H).

Step 2: Preparation of 2-((4-methylpiperidin-4-yl)oxy)pyridineDihydrochloride

To a solution of tert-butyl4-methyl-4-(pyridin-2-yloxy)piperidine-1-carboxylate (assumed 301 mg,1.03 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in MeOH andtreated with then treated with 4 N HCl in dioxanes (4 mL). The solutionwas stirred at ambient temperature for 5 min. The reaction wasconcentrated in vacuo to provide the title compound as a dihydrochloridesalt (221 mg, 100% yield) in sufficient purity for step 3. H NMR (400MHz, dc-DMSO) δ 8.12 (d, 1H), 7.69 (dd, 1H), 6.97 (dd, 1H), 6.84 (d,1H), 3.26 (m, 4H), 2.74 (m, 2H), 1.89 (m, 2H), 1.64 (s, 3H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-methyl-4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25 mg, 0.077 mmol) and2-((4-methylpiperidin-4-yl)oxy)pyridine dihydrochloride (44 mg, 0.17mmol) in DMA (0.3 mL) was added TEA (84 μL, 0.61 mmol). The reactionmixture was stirred overnight at 105° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withsaturated NaHCO_(3(aq)), water, and brine. The organic extracts weredried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (5.6 mg, 15% yield). (400 MHz,CDCl3) δ 8.32 (d, 1H), 8.19 (s, 1H), 8.12 (m, 2H), 7.69 (dd, 1H), 7.54(m, 1H). 7.13 (d, 1H), 6.83 (m, 1H), 6.78 (d, 1H), 6.72 (d, 1H), 4.08(m, 2H), 3.85 (s, 3H), 3.36 (m, 2H), 2.57 (m, 2H), 1.79 (m, 2H), 1.70(s, 3H), 1.39 (s, 6H).

Example 256

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((5-methoxypyrazin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-methoxypyrazin-2-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(278 mg, 1.38 mmol) in DMF (1.7 mL) was added sodium hydride (60% w/w,61 mg, 1.52 mmol). The reaction was stirred for 5 min at ambienttemperature. Then 2-chloro-5-methoxypyrazine (100 mg, 0.692 mmol) wasadded and reaction stirred overnight at 95° C. The reaction was cooledto ambient temperature and diluted with DCM and washed with saturatedNaHCO_(3(aq)), water, and brine. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The residue was purified by silica chromatography (5-40% EtOAc inhexanes as the gradient eluent) to afford the title compound (assumedquantitative yield, 214 mg) in sufficient purity for step 2. MS (apci)m/z=210.1 (M−Boc).

Step 2: Preparation of 2-methoxy-5-(piperidin-4-yloxy)pyrazineDihydrochloride

To a solution of tert-butyl4-((5-methoxypyrazin-2-yl)oxy)piperidine-1-carboxylate (assumed 214 mg,0.692 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in MeOH andtreated with treated with 4 N HCl in dioxanes (4 mL). The solution wasstirred at ambient temperature for 5 min. The reaction was concentratedin vacuo to provide the title compound as a dihydrochloride salt (61.3mg, 21.7% yield) in sufficient purity for step 3. MS (apci) m/z=210.1(M+H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((5-methoxypyrazin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 32 mg, 0.098 mmol) and2-methoxy-5-(piperidin-4-yloxy)pyrazine dihydrochloride (61 mg, 0.216mmol) in DMA (0.3 mL) was added TEA (107 μL, 0.784 mmol). The reactionmixture was stirred overnight at 95° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withsaturated NaHCO_(3(aq)), water, and brine. The organic extracts weredried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (16.7 mg, 33% yield). MS (apci)m/z=516.25 (M+H).

Example 257

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((2-methoxypyrimidin-5-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((2-methoxypyrimidin-5-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (222 mg, 0.793 mmol) and2-methoxypyrimidin-5-ol (100 mg, 0.793 mmol) in DMF (2 mL) was addedpotassium carbonate (219 mg, 1.59 mmol) and then the reaction mixturewas stirred overnight at 95° C. After cooling to ambient temperature,the reaction mixture was diluted with DCM and washed with saturatedNaHCO_(3(aq)), water, and brine. The organic extracts were dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo to afford thetitle compound (assumed theoretical yield, 245 mg) in sufficient purityfor step 2. MS (apci) m/z=254.1 (M-t-bu).

Step 2: Preparation of 2-methoxy-5-(piperidin-4-yloxy)pyrimidineDihydrochloride

To a solution of tert-butyl4-((2-methoxypyrimidin-5-yl)oxy)piperidine-1-carboxylate (assumed 245mg, 0.793 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 45 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was treated with 4 N HCl indioxanes (4 mL). The solution was stirred at ambient temperature for 5min. The reaction was concentrated in vacuo to provide the titlecompound as a dihydrochloride salt (166 mg, 74.2% yield) in sufficientpurity for step 3. MS (apci) m/z=210.2 (M+H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((2-methoxypyrimidin-5-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 31 mg, 0.096 mmol)2-methoxy-5-(piperidin-4-yloxy)pyrimidine dihydrochloride (81 mg, 0.287mmol) in DMA (0.3 mL) was added TEA (105 μL, 0.765 mmol). The reactionmixture was stirred overnight at 95° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withsaturated NaHCO_(3(aq)), water, and brine. The organic extracts weredried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (9.6 mg, 20% yield).

Example 258

4-(6-(4-((5-fluoro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-fluoro-6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (197 mg, 0.706 mmol) and5-fluoro-6-methoxypyridin-3-ol (101 mg, 0.706 mmol) in DMF (1.8 mL) wasadded potassium carbonate (195 mg, 1.41 mmol) and then the reactionmixture was stirred for 60 h at 95° C. After cooling to ambienttemperature, the reaction mixture was diluted with saturatedNaHCO_(3(aq)) and extracted with EtOAc. The organic extracts were washedwith water and brine. The organic extracts were dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo to afford the titlecompound (assumed theoretical yield, 230 mg) in sufficient purity forstep 2. MS (apci) m/z=227.1 (M−Boc).

Step 2: Preparation of 3-fluoro-2-methoxy-5-(piperidin-4-yloxy)pyridine

To a solution of tert-butyl4-((5-fluoro-6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate (assumed230 mg, 0.706 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 45 min at ambient temperature, andthen concentrated in vacuo. The residue was purified by silicachromatography (1-9% MeOH in DCM with 0.1-0.9% NH₄OH as the gradienteluent) to afford the title compound (86 mg, 54% yield over two steps)in sufficient purity for step 3. MS (apci) m/z=227.10 (M+H).

Step 3: Preparation of4-(6-(4-((5-fluoro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 33 mg, 0.102 mmol) and3-fluoro-2-methoxy-5-(piperidin-4-yloxy)pyridine (86 mg, 0.380 mmol) inDMA (0.3 mL) was added TEA (97 μL, 0.712 mmol). The reaction mixture wasstirred overnight at 105° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc and washed with saturatedNaHCO_(3(aq)), water, and brine. The organic extracts were dried overanhydrous Na₂SO₄(s), filtered and concentrated in vacuo. The residue wassuspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (36 mg, 67% yield). MS (apci)m/z=533.20 (M+H).

Example 259

4-(6-(4-((6-(difluoromethoxy)pyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((6-(difluoromethoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (133 mg, 0.475 mmol) and6-(difluoromethoxy)pyridin-3-ol (76.5 mg, 0.475 mmol) in DMF (1.2 mL)was added potassium carbonate (197 mg, 1.42 mmol) and then the reactionmixture was stirred overnight at 95° C. After cooling to ambienttemperature, the reaction mixture was diluted with saturatedNaHCO_(3(aq)) and extracted with EtOAc. The organic extracts were washedwith water and brine. The organic extracts were dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo to afford the titlecompound (assumed theoretical yield, 164 mg) in sufficient purity forstep 2. MS (apci) m/z=245.10 (M−Boc).

Step 2: Preparation of 2-(difluoromethoxy)-5-(piperidin-4-yloxy)pyridine

To a solution tert-butyl4-((6-(difluoromethoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate(assumed 164 mg, 0.706 mmol) in 2 mL DCM was treated with TFA (2 mL, 26mmol). The reaction mixture was stirred for 45 min at ambienttemperature, and then concentrated in vacuo. The residue was purified bysilica chromatography (1-9% MeOH in DCM with 0.1-0.9% NH₄OH as thegradient eluent) to afford the title compound (61 mg, 53% yield over twosteps) in sufficient purity for step 3. MS (apci) m/z=245.10 (M+H).

Step 3: Preparation of4-(6-(4-((6-(difluoromethoxy)pyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 31 mg, 0.095 mmol) and2-(difluoromethoxy)-5-(piperidin-4-yloxy)pyridine (61 mg, 0.25 mmol) inDMA (0.32 mL) was added TEA (65 μL, 0.477 mmol). The reaction mixturewas stirred overnight at 95° C. After cooling to ambient temperature,the reaction mixture was diluted with EtOAc and washed with water andbrine. The organic extracts were dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo. The residue was suspended in 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with DCM.The combined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (21 mg, 41% yield). MS (apci) m/z=551.20 (M+H).

Example 260

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(2-isopropoxyethoxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 35 mg, 0.106 mmol) and4-[2-(propan-2-yloxy)ethoxy]piperidine HCl (71 mg, 0.319 mmol) in DMA(0.35 mL) was added TEA (102 μL, 0.744 mmol). The reaction mixture wasstirred overnight at 95° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc and washed with water and brine.The organic extracts were dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (52.5 mg, 66% yield). MS (apci) m/z=494.20 (M+H).

The compounds in Table MM were prepared using a similar method to thatdescribed for the synthesis of Example 260, replacing4-[2-(propan-2-yloxy)ethoxy]piperidine HCl with the appropriatepiperidine nucleophile. Reactions were monitored for completion by LCMS,and reaction durations were adjusted accordingly. Title compounds werecleanly isolated following chromatographic purification using anappropriate gradient eluent (and if necessary converted to the freebase).

TABLE MM MS Ex. # Structure Chemical Name m/z 261

4-(6-(4- (benzyloxy)piperidin-1- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 498.20 (M + H) 262

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- (pyridin-2-ylmethoxy)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 499.20 (M + H) 263

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- ((pyridin-2-yloxy)methyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 499.20 (M + H)

Example 264

4-(6-(4-((5-chloro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-chloro-6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (186 mg, 0.664 mmol) and5-chloro-6-methoxypyridin-3-ol (106 mg, 0.664 mmol) in DMF (1.7 mL) wasadded potassium carbonate (275 mg, 1.99 mmol) and then the reactionmixture was stirred overnight at 105° C. After cooling to ambienttemperature, the reaction mixture was diluted with saturatedNaHCO_(3(aq)) and extracted with EtOAc. The organic extracts were washedwith water and brine. The organic extracts were dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo to afford the titlecompound (assumed theoretical yield, 228 mg) in sufficient purity forstep 2. MS (apci) m/z=243.10 (M−Boc).

Step 2: Preparation 3-chloro-2-methoxy-5-(piperidin-4-yloxy)pyridine

To a solution tert-butyl4-((5-chloro-6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate (assumed228 mg, 0.664 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 15 min at ambient temperature, andthen concentrated in vacuo. The residue was purified by silicachromatography (1-9% MeOH in DCM with 0.1-0.9% NH₄OH as the gradienteluent) to afford the title compound (65 mg, 40% yield over two steps)in sufficient purity for step 3. MS (apci) m/z=243.10 (M+H).

Step 3: Preparation of4-(6-(4-((5-chloro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 26 mg, 0.079 mmol) and3-chloro-2-methoxy-5-(piperidin-4-yloxy)pyridine (82 mg, 0.338 mmol) inDMA (0.26 mL) was added TEA (76 μL, 0.553 mmol). The reaction mixturewas stirred 1 h at 95° C. After cooling to ambient temperature, thereaction mixture was diluted with 60:40 ACN:water containing 2% TFA. Thesolution was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (12 mg, 28% yield).MS (apci) m/z=549.15 (M+H).

Example 265

4-(6-(4-((5-fluoropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-fluoropyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (257 mg, 0.920 mmol) and3-fluoro-5-hydroxypyridine (104 mg, 0.920 mmol) in DMF (2.3 mL) wasadded potassium carbonate (381 mg, 2.76 mmol) and then the reactionmixture was stirred overnight at 105° C. After cooling to ambienttemperature, the reaction mixture was diluted with saturatedNaHCO_(3(aq)) and extracted with EtOAc. The organic extracts were washedwith water and brine. The organic extracts were dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo to afford the titlecompound (assumed theoretical yield, 273 mg) in sufficient purity forstep 2. MS (apci) m/z=297.2 (M+H).

Step 2: Preparation 3-fluoro-5-(piperidin-4-yloxy)pyridine

To a solution tert-butyl4-((5-fluoropyridin-3-yl)oxy)piperidine-1-carboxylate (assumed 273 mg,0.920 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 15 min at ambient temperature, and thenconcentrated in vacuo. The residue was purified by silica chromatography(1-9% MeOH in DCM with 0.1-0.9% NH₄OH as the gradient eluent) to affordthe title compound (89 mg, 49% yield over two steps) in sufficientpurity for step 3. MS (apci) m/z=197.10 (M+H).

Step 3: Preparation of4-(6-(4-((5-fluoropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[methyl1,5-a]pyridine-3-carbonitrile (Intermediate P42; 25.5 mg, 0.078 mmol)and 3-fluoro-5-(piperidin-4-yloxy)pyridine (15.3 mg, 0.781 mmol) in DMA(0.26 mL) was added TEA (75 μL, 0.547 mmol). The reaction mixture wasstirred 1 h at 95° C. After cooling to ambient temperature, the reactionmixture was diluted with 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (12 mg, 31% yield). MS (apci)m/z=503.25 (M+H).

Example 266

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((4-methoxypyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((4-methoxypyridin-2-yl)oxy)piperidine-1-carboxylate

To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(146 mg, 0.725 mmol) in DMF (2.4 mL) was added sodium hydride (60% w/w,37.7 mg, 0.943 mmol). The reaction was stirred for 10 min at ambienttemperature. Then 2-chloro-4-methoxypyridine (104 mg, 0.725 mmol) wasadded and reaction stirred 92 h at 95° C. The reaction was cooled toambient temperature and diluted with water and extracted with EtOAc.Combined organics were washed with saturated NaHCO_(3(aq)), water, andbrine. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (assumed quantitative yield, 224 mg) in sufficient purity forstep 2. MS (apci) m/z=309.1 (M+H).

Step 2: Preparation of 4-methoxy-2-(piperidin-4-yloxy)pyridine

To a solution tert-butyl4-((4-methoxypyridin-2-yl)oxy)piperidine-1-carboxylate (assumed 224 mg,0.725 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 20 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in DCM and thesolution was purified by silica chromatography (1-9% MeOH in DCM with0.1-0.9% NH₄OH as the gradient eluent) to afford the title compound (54mg, 36% yield over two steps) in sufficient purity for step 3. MS (apci)m/z=209.1 (M+H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((4-methoxypyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25 mg, 0.077 mmol) and4-methoxy-2-(piperidin-4-yloxy)pyridine (16 mg, 0.077 mmol) in DMA (0.3mL) was added TEA (73 μL, 0.54 mmol). The reaction mixture was stirredovernight at 95° C. After cooling to ambient temperature, the reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic extracts were washed with saturated NaHCO_(3(aq)), water, andbrine. The organic extracts were dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo. The residue was suspended in 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with DCM.The combined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (16.7 mg, 33% yield). MS (apci) m/z=515.20 (M+H).

Example 267

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridazin-3-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-(pyridazin-3-yloxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(140 mg, 0.696 mmol) in DMF (2.3 mL) was added sodium hydride (60% w/w,56 mg, 1.39 mmol). The reaction was stirred for 10 min at ambienttemperature. Then 3-chloropyridazine (159 mg, 1.39 mmol) was added andreaction stirred 3 h at 95° C. The reaction was cooled to ambienttemperature and diluted with water and extracted with EtOAc. Combinedorganics were washed with saturated NaHCO_(3(aq)), water, and brine. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo to afford the title compound (assumedquantitative yield, 194 mg) in sufficient purity for step 2. MS (apci)m/z=280.2 (M+H).

Step 2: Preparation of 3-(piperidin-4-yloxy)pyridazine

To a solution of tert-butyl4-(pyridazin-3-yloxy)piperidine-1-carboxylate (assumed 194 mg, 0.696mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). The reactionmixture was stirred for 20 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in DCM and thesolution was purified by silica chromatography (1-9% MeOH in DCM with0.1-0.9% NH₄OH as the gradient eluent) to afford the title compound (111mg, 89% yield over two steps) in sufficient purity for the next step. MS(apci) m/z=180.1 (M+H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridazin-3-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 28 mg, 0.086 mmol) and3-(piperidin-4-yloxy)pyridazine (46 mg, 0.257 mmol) in DMA (0.3 mL) wasadded TEA (82 μL, 0.601 mmol). The reaction mixture was stirredovernight at 95° C. After cooling to ambient temperature, the reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic extracts were washed with saturated NaHCO_(3(aq)), water, andbrine. The organic extracts were dried over anhydrous Na₂SO₄(s),filtered and concentrated in vacuo. The residue was suspended in 60:40ACN:water containing 2% TFA. The solution was purified directly by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was treated with saturated NaHCO_(3(aq)) and extracted with DCM.The combined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (23.5 mg, 56% yield). MS (apci) m/z=486.20 (M+H).

Example 268

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxy-5-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((6-methoxy-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(761 mg, 3.78 mmol) in DMF (7.9 mL) was added sodium hydride (60% w/w,164 mg, 4.10 mmol). The reaction was stirred for 5 min at ambienttemperature. Then 6-chloro-3-methoxy-4-methylpyridazine (500 mg, 3.15mmol) was added and reaction stirred overnight at 95° C. The reactionwas cooled to ambient temperature and diluted with water and extractedwith EtOAc. Combined organics were washed with saturated NaHCO_(3(aq)),water, and brine. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (assumed quantitative yield, 1.019 g) in sufficientpurity for step 2. MS (apci) m/z=324.1 (M+H).

Step 2: Preparation of3-methoxy-4-methyl-6-(piperidin-4-yloxy)pyridazine

To a solution of tert-butyl4-((6-methoxy-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate(assumed 1.019 g, 3.15 mmol) in 2 mL DCM was treated with TFA (2 mL, 26mmol). The reaction mixture was stirred for 20 min at ambienttemperature, and then concentrated in vacuo. The crude residue wasresuspended in DCM and the solution was purified by silicachromatography (1-9% MeOH in DCM with 0.1-0.9% NH₄OH as the gradienteluent) to afford the title compound (70 mg, 10% yield over two steps)in sufficient purity for step 3. MS (apci) m/z=224.15 (M+H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxy-5-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 51 mg, 0.156 mmol) and3-methoxy-4-methyl-6-(piperidin-4-yloxy)pyridazine (70 mg, 0.314 mmol)in DMA (0.8 mL) was added TEA (150 μL, 1.09 mmol). The reaction mixturewas stirred 40 h at 95° C. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted with EtOAc. Thecombined organic extracts were washed with saturated NaHCO_(3(aq)),water, and brine. The organic extracts were dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was suspendedin 60:40 ACN:water containing 2% TFA. The solution was purified directlyby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted withDCM. The combined organic extracts were washed with brine, then driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (26.5 mg, 32% yield). MS (apci) m/z=530.30(M+H).

Example 269

4-(6-(4-((5-ethylpyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((5-ethylpyridin-2-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(1.42 g, 7.06 mmol) in DMF (11.8 mL) was added sodium hydride (60% w/w,311 mg, 7.77 mmol). The reaction was stirred for 15 min at ambienttemperature. Then 2-chloro-5-ethylpyridine (1.00 g, 3.15 mmol) was addedand reaction stirred 48 h at 90° C. The reaction was cooled to ambienttemperature and additional tert-Butyl4-hydroxy-4-methylpiperidine-1-carboxylate (1.42 g, 7.06 mmol) andsodium hydride (60% w/w, 311 mg, 7.77 mmol) were added. The reaction wasstirred for 60 h at 90° C. The reaction was cooled to ambienttemperature and additional tert-Butyl4-hydroxy-4-methylpiperidine-1-carboxylate (1.42 g, 7.06 mmol) andsodium hydride (60% w/w, 311 mg, 7.77 mmol) were added. The reaction wasstirred for 4 h at 90° C. The reaction was cooled to ambient temperatureand diluted with water and saturated NaHCO_(3(aq)) and extracted withEtOAc. Combined organics were washed with water and brine. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The crude residue was resuspended in DCM and thesolution was purified by silica chromatography (5-50% EtOAc in Hexanesas the gradient eluent) to afford the title compound (assumedquantitative yield, 2.163 g) in sufficient purity for step 2. MS (apci)m/z=307.2 (M+H).

Step 2: Preparation of 5-ethyl-2-(piperidin-4-yloxy)pyridine

To a solution of tert-butyl4-((5-ethylpyridin-2-yl)oxy)piperidine-1-carboxylate (assumed 2.163 g,7.06 mmol) in 5 mL DCM was treated with TFA (10 mL, 130 mmol). Thereaction mixture was stirred for 20 min at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in DCM and thesolution was purified by silica chromatography (1-9% MeOH in DCM with0.1-0.9% NH₄OH as the gradient eluent) to afford the title compound (835mg, 57% yield over two steps) in sufficient purity for step 3. MS (apci)m/z=207.20 (M+H).

Step 3: Preparation of4-(6-(4-((5-ethylpyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[ethyl1,5-a]pyridine-3-carbonitrile (Intermediate P42; 25 mg, 0.077 mmol) and5-ethyl-2-(piperidin-4-yloxy)pyridine (55 mg, 0.27 mmol) in DMA (0.8 mL)was added TEA (73 μL, 0.54 mmol). The reaction mixture was stirred 40 hat 95° C. After cooling to ambient temperature, the reaction mixture wasdiluted with water and extracted with EtOAc. The combined organicextracts were washed with water and brine. The organic extracts weredried over anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was suspended in 60:40 ACN:water containing 2% TFA. The solutionwas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (6.7 mg, 17% yield). MS (apci)m/z=513.30 (M+H).

Example 270

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((6-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(313 mg, 1.56 mmol) in DMF (1.94 mL) was added sodium hydride (60% w/w,68.4 mg, 1.71 mmol). The reaction was stirred for 5 min at ambienttemperature. Then 3-chloro-6-methylpyridazine (100 mg, 0.778 mmol) wasadded and reaction stirred overnight at 95° C. The reaction was cooledto ambient temperature and diluted with saturated NaHCO_(3(aq)) andextracted with EtOAc. Combined organics were washed with water andbrine. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (assumed quantitative yield, 228 mg) in sufficient purity forstep 2. MS (apci) m/z=294.20 (M+H).

Step 2: 3-methyl-6-(piperidin-4-yloxy)pyridazine

To a solution of tert-butyl4-((6-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate (assumed 228 mg,0.778 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in DCM and thesolution was purified by silica chromatography (1-9% MeOH in DCM with0.1-0.9% NH₄OH as the gradient eluent) to afford the title compound (104mg, 69% yield over two steps) in sufficient purity for step 3. MS (apci)m/z=194.1 (M+H).

Step 3: Preparation of6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 32 mg, 0.098 mmol) and3-methyl-6-(piperidin-4-yloxy)pyridazine (57 mg, 0.29 mmol) in DMA (0.3mL) was added TEA (67 μL, 0.49 mmol). The reaction mixture was stirredovernight at 95° C. After cooling to ambient temperature, the reactionmixture was diluted with EtOAc and washed with water and brine. Theorganic extracts were dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was suspended in 60:40 ACN:watercontaining 2% TFA. The solution was purified directly by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with DCM. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (25 mg, 51% yield). MS (apci) m/z=500.20 (M+H). ¹H NMR(400 MHz, CDCl₃) δ 8.35 (d, 1H), 8.20 (s, 1H), 8.15 (d, 1H), 7.72 (dd,1H), 7.24 (d, 1H). 7.15 (d, 1H), 6.87 (d, 1H), 6.82 (d, 1H), 5.56 (m,1H), 4.10 (m, 2H), 3.86 (s, 2H), 3.51 (m, 2H), 2.61 (s, 3H), 2.23 (m,2H), 1.91 (m, 2H), 1.39 (s, 6H).

Example 271

4-(6-(4-(4-chlorophenoxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 25.5 mg, 0.078 mmol) and4-(4-chlorophenoxy)piperidine hydrochloride (38.8 mg, 0.156 mmol) in DMA(0.5 mL) was added TEA (33 μL, 0.234 mmol). The reaction mixture wasstirred overnight at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with DCM and washed with water and brine.The organic extracts were dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated Na₂CO_(3(aq)) and extracted with DCM. The combinedorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (28 mg, 70% yield). MS (apci) m/z=518.1 (M+H).

Example 272

4-(6-(4-(4-cyanophenoxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared using a similar method to that describedfor the synthesis of Example 271, replacing4-(4-chlorophenoxy)piperidine hydrochloride with4-(piperidin-4-yloxy)benzonitrile. MS (apci) m/z=509.2 (M+H).

Example 273

4-(6-(4-(3-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 28 mg, 0.085 mmol) and 4-(3-fluorophenoxy)piperidinehydrochloride (39 mg, 0.170 mmol) in DMA (0.6 mL) was added TEA (47 μL,0.34 mmol). The reaction mixture was stirred overnight at 90° C. Aftercooling to ambient temperature, the reaction mixture was diluted withDCM and washed with water and brine. The organic extracts were driedover anhydrous Na₂SO₄(s), filtered and concentrated in vacuo. Theresidue was purified by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated Na₂CO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (25.5 mg, 60% yield). MS (apci)m/z=502.2 (M+H).

Example 274

4-(6-(4-(2-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared using a similar method to that describedfor the synthesis of Example 273, replacing4-(3-fluorophenoxy)piperidine hydrochloride with4-(2-fluorophenoxy)piperidine. MS (apci) m/z=502.2 (M+H).

Example 275

4-(6-(4-(2-cyanophenoxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 27 mg, 0.083 mmol) and2-(piperidin-4-yloxy)benzonitrile (34 mg, 0.166 mmol) in DMA (0.42 mL)was added TEA (70 μL, 0.498 mmol). The reaction mixture was stirredovernight at 95° C. After cooling to ambient temperature, the reactionmixture was diluted with DCM and washed with water and brine. Theorganic extracts were dried over anhydrous Na₂SO₄(s), filtered andconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated Na₂CO_(3(aq)) and extracted with DCM. The combinedorganic extracts were washed with brine, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (23 mg, 55% yield). MS (apci) m/z=509.2 (M+H).

Example 276

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-methoxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 26.1 mg, 0.08 mmol) in DMA (1 mL) was added4-methoxy-piperidine (9.7 mg, 0.084 mmol) followed by TEA (54 μL, 0.40mmol). The reaction mixture was stirred overnight at 90° C. The reactionwas cooled to ambient temperature and additional 4-methoxypiperidine (5mg, 0.04 mmol) was added. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted with EtOAc.Combined organic extracts were washed with water and brine. The organicextracts were dried over anhydrous Na₂SO₄(s), filtered and concentratedin vacuo. The residue was purified by silica chromatography (5-50%Acetone in DCM as the gradient eluent). Fractions containing the productwere concentrated in vacuo and repurified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated Na₂CO_(3(aq)) and extracted with 4:1 DCM:IPA. Thecombined organic extracts were washed with brine, then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (23 mg, 55% yield). MS (apci) m/z=422.2 (M+H).

Example 277

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 50 mg, 0.15 mmol) and1-methyl-2-(piperidin-4-yl)-1H-benzo[d]imidazole dihydrochloride (66 mg,0.23 mmol) and DIEA (133 μL, 0.77 mmol) were combined in DMSO (306 μL).The reaction mixture was stirred 72 h at 90° C. After cooling to ambienttemperature, the reaction mixture was purified directly by C18 reversephase chromatography (5-45% ACN in water as the gradient eluent) toafford the title compound (38 mg, 47% yield). MS (apci) m/z=522.2 (M+H).

Example 278

4-(6-(4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared using a similar method to that describedfor the synthesis of Example 277, replacing1-methyl-2-(piperidin-4-yl)-1H-benzo[d]imidazole dihydrochloride with2-(piperidin-4-yl)-1H-benzo[d]imidazole. MS (apci) m/z=508.2 (M+H).

Example 279

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-isobutylpiperidine-4-carboxamideStep 1: Preparation tert-butyl4-ethyl-4-(isobutylcarbamoyl)piperidine-1-carboxylate

A mixture of 1-(tert-butoxycarbonyl)-4-ethylpiperidine-4-carboxylic acid(260 mg, 1.01 mmol), HATU (461 mg, 1.21 mmol), and2-methylpropan-1-amine (81 mg, 1.11 mmol) in DMF (4 mL) was treated withDIEA (352 μL, 2.0 mmol) and then stirred for 60 h at 60° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc and washed with water and brine. The combined organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered and concentrated invacuo. The residue was purified by silica chromatography (0-95% EtOAc inHexanes as the gradient eluent) to afford the title compound (assumedtheoretical yield, 316 mg) in sufficient purity for step 2. MS (apci)m/z=256.2 (M-Bu^(t)).

Step 2: Preparation of 4-ethyl-N-isobutylpiperidine-4-carboxamide

A solution of tert-butyl4-ethyl-4-(isobutylcarbamoyl)piperidine-1-carboxylate (assumed 316 mg,1.01 mmol) in 2 mL DCM was treated with TFA (2 mL, 26 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was diluted with 4:1 DCM: IPAand washed with saturated NaHCO_(3(aq)). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (101 mg, 84% yield over two steps) insufficient purity for step 3. MS (apci) m/z=213.2 (M+H).

Step 3: Preparation of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-isobutylpiperidine-4-carboxamide.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 20 mg, 0.06 mmol) and4-ethyl-N-phenylpiperidine-4-carboxamide (42 mg, 0.18 mmol) in DMA (0.25mL) was added TEA (41 μL, 0.30 mmol). The reaction mixture was stirred14 h at 90° C. After cooling to ambient temperature, the reactionmixture was diluted with EtOAc and washed with water and brine. Theorganic extracts were dried over anhydrous Na2SO4(s), filtered andconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO_(3(aq)) and extracted with 4:1 DCM:IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was repurified by silicachromatography (0-30% MeOH in DCM with 0-2% NH₄OH as the gradienteluent) to cleanly provide the title compound (21 mg, 65% yield) MS(apci) m/z=519.3 (M+H).

Example 280

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-ylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 38 mg, 0.117 mmol) N-(piperidin-4-yl)pyridin-2-amine(42 mg, 0.235 mmol) in DMA (0.78 mL) was added TEA (98 μL, 0.70 mmol).The reaction mixture was stirred overnight at 90° C. After cooling toambient temperature, the reaction mixture was diluted with DCM andwashed with water and brine. The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The residuewas purified by C18 reverse phase chromatography (5-95% ACN in waterwith 0.1% TFA as the gradient eluent) to afford the title compound asthe TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq)) andextracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo tocleanly provide the title compound (11 mg, 20% yield) MS (apci)m/z=484.2 (M+H).

Example 281

6-(2-hydroxy-2-methylpropoxy)-4-(6-((1R,5S,6r)-6-(pyrimidin-2-ylamino)-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-(6-((1R,5S,6r)-6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P63; 25 mg, 0.051 mmol) and2-chloropyrimidine (8.7 mg, 0.076 mmol) in DMSO (102 μL) was added DIEA(44 μL, 0.25 mmol). The reaction mixture was stirred 60 h at 90° C.After cooling to ambient temperature, the reaction was purified directlyby C18 reverse phase chromatography (5-40% ACN in water as the gradienteluent) to afford the title compound (9.5 mg, 38% yield) MS (apci)m/z=497.25 (M+H).

The compounds in Table NN were prepared using a similar method to thatdescribed for the synthesis of Example 281, replacing 2-chloropyrimidinewith the appropriate halogenated heterocycle. Reactions were monitoredfor completion by LCMS, and reaction durations were adjustedaccordingly. Title compounds were cleanly isolated followingchromatographic purification using an appropriate gradient eluent (andif necessary converted to the free base).

TABLE NN MS Ex. # Structure Chemical Name m/z 282

6-(2-hydroxy-2- methylpropoxy)-4-(6- ((1R,5S,6r)-6-((5-methylpyrimidin-2- yl)amino)-3- azabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 511.2 (M + H) 283

6-(2-hydroxy-2- methylpropoxy)-4-(6- ((1R,5S,6r)-6-(pyridin-2-ylamino)-3- azabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 496.1 (M + H) 284

4-(6-((1R,5S,6r)-6-((3- chloropyridin-2-yl)amino)-3-azabicyclo[3.1.1]heptan- 3-yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 530.1 (M + H) 285

6-(2-hydroxy-2- methylpropoxy)-4-(6- ((1R,5S,6r)-6-((2-methylpyrimidin-4- yl)amino)-3- azabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 511.2 (M + H) 286

4-(6-((1R,5S,6r)-6-((3- fluoro-6-methylpyridin-2- yl)amino)-3-azabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 475.2 (M + H)497.1 (M + Na)

Example 287

N-((1R,5S,6r)-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)benzamide

A mixture of4-(6-((1R,5S,6r)-6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P63; 25 mg, 0.051 mmol), HATU (21 mg,0.056 mmol), and benzoic acid (7 mg, 0.061 mmol) in DMSO (254 μL) wastreated with DIEA (44 μL, 0.254 mmol) and then stirred for 2 min atambient temperature. The reaction was purified directly by C18 reversephase chromatography (5-50% ACN in water as the gradient eluent) toafford the title compound (22.8 mg, 86% yield) MS (apci) m/z=523.2(M+H), 545.2 (M+Na).

Example 288

N-((1R,5S,6r)-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)picolinamide

The title compound was prepared using a similar method to that describedfor the synthesis of Example 287, replacing benzoic acid with picolinicacid. MS m/z=524.2 (M+H), 546.2 (M+Na)

Example 289

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)benzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P64; 20 mg, 0.049 mmol), HATU (21 mg, 0.054 mmol), andbenzoic acid (9 mg, 0.24 mmol) in DCM (0.5 mL) was treated with DIEA (43μL, 0.054 mmol) and then stirred for 1 h at ambient temperature. Thereaction mixture was concentrated in vacuo. The residue was suspended in60:40 ACN:water containing 2% TFA. The solution was purified directly byC18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted withDCM. The combined organic extracts were washed with brine, then driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (43.7 mg, 49.3% yield). MS (apci) m/z=511.20(M+H).

The compounds in Table OO were prepared using a similar method to thatdescribed for the synthesis of Example 289, replacing benzoic acid withthe appropriate carboxylic acid. Reactions were monitored for completionby LCMS, and reaction durations were adjusted accordingly. Titlecompounds were cleanly isolated following chromatographic purificationusing an appropriate gradient eluent (and if necessary converted to thefree base).

TABLE OO MS Ex. # Structure Chemical Name m/z 290

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)piperidin-4-yl)-3- fluorobenzamide 529.20(M + H) 291

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)piperidin-4- yl)isobutyramide 477.20 (M +H) 292

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)piperidin-4- yl)picolinamide 512.20 (M + H)293

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)piperidin-4- yl)nicotinamide 512.20 (M + H)

Example 294

N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-4-fluorobenzamide

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P64; 20 mg, 0.049 mmol), HATU (21 mg, 0.054 mmol), and4-fluorobenzoic acid (69 mg, 0.049 mmol) in DCM (0.5 mL) was treatedwith DIEA (43 μL, 0.049 mmol) and then stirred for 2.5 h at ambienttemperature. The reaction mixture was concentrated in vacuo. The residuewas suspended in 60:40 ACN:water containing 2% TFA. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo to afford the title compound (16 mg, 60% yield). MS (apci)m/z=529.20 (M+H).

Example 295

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-methylpiperidine-4-carboxamide

A mixture of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid (Intermediate P65; 30 mg, 0.067 mmol), HATU (31 mg, 0.080 mmol),and isobutylamine (6 mg, 0.08 mmol) in DCM (133 μL) was treated withDIEA (35 μL, 0.2 mmol) and then stirred for 2 h at ambient temperature.The reaction mixture was concentrated in vacuo. The residue was purifieddirectly by C18 reverse phase chromatography (5-95% ACN in water with 1%TFA as the gradient eluent) to afford the title compound as the TFAsalt. The TFA salt was treated with saturated NaHCO_(3(aq)) andextracted with DCM. The combined organic extracts were washed withbrine, then dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo. The residue was triturated with DCM/Hexanes and concentratedin vacuo to afford the title compound (12 mg, 36% yield). MS (apci)m/z=505.3 (M+H).

Example 296

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-((tetrahydrofuran-2-yl)methyl)piperidine-4-carboxamide

A mixture of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid (Intermediate P65; 30 mg, 0.067 mmol), HATU (30 mg, 0.080 mmol),and (tetrahydrofuran-2-yl)methanamine (7 mg, 0.067 mmol) in DCM (133 μL)was treated with DIEA (35 μL, 0.20 mmol) and then stirred for overnightat ambient temperature. The reaction mixture was concentrated in vacuo.The residue was purified directly by C18 reverse phase chromatography(5-95% ACN in water with 1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with DCM. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was triturated with DCM/Hexanes andconcentrated in vacuo to afford the title compound (24 mg, 67% yield).MS (apci) m/z=533.3 (M+H).

The compounds in Table PP were prepared using a similar method to thatdescribed for the synthesis of Example 296, replacing(tetrahydrofuran-2-yl)methanamine with the appropriate amine. Reactionswere monitored for completion by LCMS, and reaction durations wereadjusted accordingly. Title compounds were cleanly isolated followingchromatographic purification using an appropriate gradient eluent (andif necessary converted to the free base).

TABLE PP MS Ex. # Structure Chemical Name m/z 297

1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methyl-N- ((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4- carboxamide 547.3 (M + H) 298

1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methyl-N- ((tetrahydro-2H-pyran-3-yl)methyl)piperidine-4- carboxamide 547.3 (M + H)

Example 299

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2,6-difluorophenyl)-4-methylpiperidine-4-carboxamideStep 1: Preparation of tert-butyl4-((2,6-difluorophenyl)carbamoyl)-4-methylpiperidine-1-carboxylate

To a solution of 2,6-difluoroaniline (226.2 μL, 2.24 mmol) in toluene(9.0 mL) was treated with trimethylaluminum (1.1 mL, 2.24 mmol) wasstirred for 15 min at ambient temperature. Then the solution was treatedwith ethyl N-Boc-4-methylpiperidine-4-carboxylate (506 mg, 1.86 mmol)and then stirred for 16 h at 70° C. The reaction was cooled to ambienttemperature and treated with 0.5 M NaK Tartrate and diluted with EtOAc.The organic solution was washed with water and brine. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified by silica chromatography(5-75% EtOAc in Hexanes as the gradient eluent) to cleanly provide thetitle compound (211 mg, 32% yield) MS (apci) m/z=343.2 (M−H).

Step 2: Preparation ofN-(2,6-difluorophenyl)-4-methylpiperidine-4-carboxamide

To a solution of tert-butyl4-((2,6-difluorophenyl)carbamoyl)-4-methylpiperidine-1-carboxylate (211mg, 0.60 mmol) in 20 μL DCM was treated with TFA (20 μL, 0.26 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo vacuo to afford the title compound as the TFAsalt. The TFA salt was treated with saturated NaHCO_(3(aq)) andextracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Theresidue was triturated with DCM/Hexanes and concentrated in vacuo toafford the title compound (107 mg, 71% yield over two steps) insufficient purity for step 3. MS (apci) m/z=255.1 (M+H).

Step 3: Preparation of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2,6-difluorophenyl)-4-methylpiperidine-4-carboxamide.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 46 mg, 0.14 mmol) andN-(2,6-difluorophenyl)-4-methylpiperidine-4-carboxamide (108 mg, 0.46mmol) in DMSO (0.564 mL) was added DIEA (74 μL, 0.42 mmol). The reactionmixture was stirred overnight at 70° C. After cooling to ambienttemperature, the reaction mixture was diluted with 4:1 DCM:IPA andwashed with water and brine. The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The residuewas purified by C18 reverse phase chromatography (5-95% ACN in waterwith 0.1% TFA as the gradient eluent) to afford the title compound asthe TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq)) andextracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Theresidue was triturated with DCM/Hexanes and concentrated in vacuo toafford the title compound (50 mg, 63% yield) MS (apci) m/z=561.3 (M+H).

Example 300

1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(5-fluoro-2-methylphenyl)-4-methylpiperidine-4-carboxamideStep 1: Preparation of tert-butyl4-((5-fluoro-2-methylphenyl)carbamoyl)-4-methylpiperidine-1-carboxylate

To a solution of 5-fluoro-2-methylaniline (586 mg, 4.68 mmol) in toluene(12.0 mL) was treated with trimethylaluminum (2.3 mL, 4.68 mmol) wasstirred for 15 min at ambient temperature. Then the solution was treatedwith 1-(tert-butyl) 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (635mg, 2.341 mmol) and then stirred for 16 h at 70° C. The reaction wascooled to ambient temperature and treated with 0.5 M NaK Tartrate anddiluted with EtOAc. The organic solution was washed with water andbrine. The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was purified by silicachromatography (5-75% EtOAc in Hexanes as the gradient eluent) tocleanly provide the title compound (266 mg, 32% yield) MS (apci)m/z=349.2 (M−H).

Step 2: Preparation ofN-(5-fluoro-2-methylphenyl)-4-methylpiperidine-4-carboxamide

To a solution of tert-butyl4-((5-fluoro-2-methylphenyl)carbamoyl)-4-methylpiperidine-1-carboxylate(211 mg, 0.60 mmol) in 25 μL DCM was treated with TFA (25 μL, 0.32mmol). The reaction mixture was stirred for 1 h at ambient temperature,and then concentrated in vacuo to afford the title compound as the TFAsalt. The TFA salt was treated with saturated NaHCO_(3(aq)) andextracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Theresidue was triturated with DCM/Hexanes and concentrated in vacuo toafford the title compound (127 mg, 64% yield over two steps) insufficient purity for step 3. MS (apci) m/z=251.1 (M+H).

Step 3: Preparation of1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(5-fluoro-2-methylphenyl)-4-methylpiperidine-4-carboxamide.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 55 mg, 0.17 mmol) andN-(5-fluoro-2-methylphenyl)-4-methylpiperidine-4-carboxamide (127 mg,0.51 mmol) in DMSO (12 μL) was added DIEA (88 μL, 0.51 mmol). Thereaction mixture was stirred overnight at 70° C. After cooling toambient temperature, the reaction mixture was diluted with 4:1 DCM:IPAand washed with water and brine. The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The residuewas purified by C18 reverse phase chromatography (5-95% ACN in waterwith 0.1% TFA as the gradient eluent) to afford the title compound asthe TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq)) andextracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Theresidue was triturated with DCM/Hexanes and concentrated in vacuo toafford the title compound (48 mg, 51% yield) MS (apci) m/z=557.3 (M+H).

Example 301

N-(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(P68, 30 mg, 0.619 mmol) in DMF (0.6 mL) was added potassium carbonate(26 mg, 0.186 mmol), followed by iodomethane (6 μL, 0.09 mmol) and wasstirred for 1 h at 60° C. The reaction was diluted with EtOAc and washedwith water and brine and dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was resuspended in DCM (2 mL) andpurified using silica chromatography 10-90% EtOAc in Hexanes to affordthe title compound (9 mg, 29% yield) MS (apci) m/z=499.2 (M+H).

Example 302

N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

Step 1: Preparation of tert-butyl3-(((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate. To a mixture ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P68; 47 mg, 0.097 mmol) and tert-butyl3-(bromomethyl)-3-fluoroazetidine-1-carboxylate (39 mg, 0.146 mmol) wasadded cesium carbonate (126 mg, 0.388 mmol) in DMA (1 mL) and wasstirred overnight at 60° C. After cooling to ambient temperature,reaction was diluted with EtOAc and washed with water and dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The residuewas purified using silica chromatography 25-50% EtOAc in Hexanes toafford the title compound (62 mg, 95% yield) MS (apci) m/z=672.3 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide.To a solution of tert-butyl3-(((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(62 mg, 0.09 mmol) in DCM (4 mL) was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 2 h at ambient temperature, andthen concentrated in vacuo. The residue was purified by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent). Fractions containing the desired product were combined, dilutedwith 4:1 DCM:iPrOH and washed sequentially with saturated NaHCO_(3(aq))and brine. The organic extracts then were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound. (42 mg, 80% yield) MS (apci) m/z=572.3 (M+H).

Example 303

N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

A mixture ofN-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 302; 30 mg, 0.053 mmol), formaldehyde (20 μL, 0.26 mmol), andNaBH(AcO)₃ (56 mg, 0.26 mmol) were dissolved in DMA (2 mL). The reactionmixture was stirred overnight at ambient temperature. The reactionmixture was diluted with EtOAc and washed with water. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent). Fractions containing the desired product were combined, dilutedwith 4:1 DCM:iPrOH and washed sequentially with saturated NaHCO_(3(aq))and brine. The organic extracts then were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (27 mg, 87% yield) MS (apci) m/z=586.3 (M+H). ¹H NMR (400 MHz,CDCl₃) δ 8.32-8.30 (m, 1H), 8.19-8.15 (m, 2H), 7.71-7.66 (m, 1H),7.17-7.13 (m, 2H), 7.06-7.02 (m, 1H), 7.00-6.94 (m, 1H), 6.80-6.77 (m,1H), 5.50 (br s, 1H), 4.36-4.29 (m, 2H), 4.05-3.92 (m, 2H), 3.75-3.57(m, 2H), 3.43-3.32 (m, 2H), 3.26-3.13 (m, 2H), 2.43 (s, 3H), 2.39 (s,3H), 2.33-2.21 (m, 2H), 1.90-1.75 (m, 2H), 1.58 (s, 3H).

Example 304

N-(1-(5-(3-cyano-6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

To a mixture ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P68; 39 mg, 0.08 mmol) and2-bromo-N,N-dimethylethan-1-amine hydrobromide (37 mg, 0.16 mmol) wasadded cesium carbonate (105 mg, 0.32 mmol) in DMA (1 mL) and was stirredovernight at 60° C. After cooling to ambient temperature, reaction wasdiluted with EtOAc and washed with water and dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The residue waspurified using silica chromatography 2-4% MeOH in DCM. Fractionscontaining the product were concentrated in vacuo. The residue wasrepurified was purified by C18 reverse phase chromatography (5-95% ACNin water with 0.1% TFA as the gradient eluent). Fractions containing thedesired product were combined, diluted with 4:1 DCM:iPrOH and washedsequentially with saturated NaHCO_(3(aq)) and brine. The organicextracts then were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (8 mg, 18% yield) MS(apci) m/z=556.3 (M+H).

The compounds in Table QQ were prepared using a similar method to thatdescribed for the synthesis of Example 304, replacing2-bromo-N,N-dimethylethan-1-amine hydrobromide with the appropriatealkyl halide. Reactions were monitored for completion by LCMS, andreaction durations were adjusted accordingly. Title compounds werecleanly isolated following chromatographic purification using anappropriate gradient eluent (and if necessary converted to the freebase).

TABLE QQ MS Ex. # Structure Chemical Name m/z 305

N-(1-(5-(3-cyano-6-(2- (pyrrolidin-1- yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)-5-fluoro-2-methylbenzamide 582.3 (M + H) 306

N-(1-(5-(3-cyano-6-(2- morpholinoethoxy)pyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4-yl)-5- fluoro-2-methylbenzamide598.3 (M + H)

Example 307

N-(1-(5-(3-cyano-6-((3-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

Step 1: Preparation of tert-butyl3-(((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-methylazetidine-1-carboxylate. To a mixture ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P68; 42 mg, 0.087 mmol) and tert-butyl3-(bromomethyl)-3-methylazetidine-1-carboxylate (34 mg, 0.13 mmol) wasadded cesium carbonate (113 mg, 0.347 mmol) in DMA (1 mL) and wasstirred overnight at 60° C. After cooling to ambient temperature,reaction was diluted with EtOAc and washed with water and the organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified using silicachromatography 50-100% EtOAc in Hexanes to afford the title compound (21mg, 36% yield) MS (apci) m/z=668.4 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-((3-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide.To a solution of tert-butyl3-(((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-methylazetidine-1-carboxylate(21 mg, 0.03 mmol) in DCM (4 mL) was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 2 h at ambient temperature, andthen concentrated in vacuo. The residue was purified by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent). Fractions containing the desired product were combined, dilutedwith 4:1 DCM:iPrOH and washed sequentially with saturated NaHCO_(3(aq))and brine. The organic extracts then were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound. (13 mg, 73% yield) MS (apci) m/z=568.3 (M+H).

Example 308

N-(1-(5-(3-cyano-6-((1,3-dimethylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

A mixture ofN-(1-(5-(3-cyano-6-((3-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 307; 12 mg, 0.021 mmol), formaldehyde (8 μL, 0.106 mmol), andNaBH(AcO)₃ (22 mg, 0.106 mmol) were dissolved in DCM (4 mL). Theresulting reaction mixture was allowed to stir overnight at roomtemperature. The reaction mixture was diluted with EtOAc and washed withwater. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA as thegradient eluent). Fractions containing the desired product werecombined, diluted with 4:1 DCM:iPrOH and washed sequentially withsaturated NaHCO_(3(aq)) and brine. The organic extracts then were driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo toafford the title compound (10 mg, 81% yield) MS (apci) m/z=582.3 (M+H).

Example 309

N-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

Step 1: Preparation of tert-butyl4-(2-((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate. To a mixture ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P68; 55 mg, 0.114 mmol), tert-Butyl4-(2-chloroethyl)tetrahydro-1(2H)-pyrazine carboxylate (57 mg, 0.227mmol) was added cesium carbonate (148 mg, 0.454 mmol) in DMA (1 mL) andwas stirred overnight at 60° C. After cooling to ambient temperature,reaction was diluted with EtOAc and washed with water and the organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified using silicachromatography (50-100% EtOAc in Hexanes) to afford the title compound(49 mg, 62% yield) MS (apci) m/z=697.4 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide.To a solution of tert-butyl4-(2-((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate(49 mg, 0.070 mmol) in DCM (4 mL) was treated with TFA (2 mL, 26 mmol).The reaction mixture was stirred for 1 h at ambient temperature, andthen concentrated in vacuo. The residue was purified by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent). Fractions containing the product were concentrated in vacuo.The residue was repurified using silica chromatography (4% MeOH in DCMwith 1% TEA as the eluent) to afford the title compound. (33 mg, 79%yield) MS (apci) m/z=597.3 (M+H).

Example 310

N-(1-(5-(3-cyano-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 309; 27 mg, 0.045 mmol) in DCM (0.25 mL) and MeOH (0.25 mL) wasadded formaldehyde (17 μL, 0.226 mmol) and NaBH(AcO)₃ (48 mg, 0.226mmol) The resulting reaction mixture was allowed to stir overnight atroom temperature. The reaction was directly purified by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with 4:1 DCM:IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The residue was triturated withDCM/Hexanes and concentrated in vacuo to afford the title compound (12.5mg, 45% yield) MS (apci) m/z=611.4 (M+H).

Example 311

(S)-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

Step 1: Preparation of tert-butyl(S)-2-(((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate. ToN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P68; 30 mg, 0.062 mmol) was added cesium carbonate (22 mg,0.068 mmol) in DMA (1.2 mL). The resulting mixture was sparged withAr_((g)) and stirred for 10 min. (S)-tert-butyl2-(bromomethyl)morpholine-4-carboxylate (26 mg, 0.093 mmol) was added tothe reaction mixture. The resulting mixture was sparged with Ar_((g))and stirred overnight at 60° C. After cooling to ambient temperature,reaction was diluted with EtOAc and washed with water and brine and theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (42 mg, 99% yield) MS(apci) m/z=684.3 (M+H).

Step 2: Preparation of(S)-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide.To a solution tert-butyl(S)-2-(((3-cyano-4-(6-(4-(5-fluoro-2-methylbenzamido)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate (42 mg, 0.061 mmol) in DCM(2 mL) was treated with TFA (0.31 mL). The reaction mixture was stirredfor 15 min at ambient temperature, and then concentrated in vacuo. Theresidue was resuspended in DCM (2 mL). The solution was purified bysilica chromatography (0.5-10% MeOH in DCM with 0.05-1% NH₄OH as thegradient eluent) to afford the title compound (6 mg, 16% yield) MS(apci) m/z=584.3 (M+H).

Example 312

3-chloro-N-(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 34 mg, 0.070 mmol) in DMF (0.7 mL) was addedpotassium carbonate (29 mg, 0.209 mmol) and then iodomethane (7 μL,0.105 mmol) was added to the reaction mixture. The resulting mixture wasstirred overnight at 60° C. After cooling to ambient temperature,reaction was diluted with DCM and purified directly using silicachromatography (0.5-10% MeOH in DCM with 0.1-2% NH₄OH as the gradienteluent). Fractions containing the product were concentrated in vacuo.The residue was diluted with EtOAc and washed with water and brine andthen dried over anhydrous Na₂SO_(4(s)), filtered and concentrated invacuo to afford the title compound (16 mg, 45% yield) MS (apci)m/z=502.2 (M+H).

Example 313

3-chloro-N-(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-N-methylpicolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Example 312; 10 mg, 0.020 mmol) in ACN (0.3 mL) was added iodomethane(4 μL, 0.06 mmol) followed by sodium hydride (1.4 mg, 0.06 mmol) andthen the reaction mixture was stirred for 1 hour at ambient temperature.The reaction was stirred for 1 hour at 85° C. After cooling to ambienttemperature, the reaction mixture was directly purified by C18 reversephase chromatography (5-95% ACN in water with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wastreated with saturated NaHCO_(3(aq)) and extracted with 4:1 DCM:IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo to afford the title compound (6.5 mg,63% yield). MS (apci) m/z=516.2 (M+H).

Example 314

3-chloro-N-(1-(5-(3-cyano-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 25 mg, 0.051 mmol) in DMF (0.5 mL) was addedpotassium carbonate (22 mg, 0.159 mmol) then4-(Chloromethyl)-1-methyl-1H-imidazole (13 mg, 0.102 mmol). Theresulting mixture was stirred 2 h at 60° C. After cooling to ambienttemperature, reaction was diluted with 60:40 ACN:water. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was dissolved in DCM (10 mL) and MeOH (1mL) and eluted through a Pl-HCO₃ resin. The organic eluent concentratedin vacuo to afford the title compound (14 mg, 45% yield). MS (apci)m/z=582.2 (M+H).

Example 315

3-chloro-N-(1-(5-(3-cyano-6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 25 mg, 0.051 mmol) in DMA (0.5 mL) was added cesiumcarbonate (52 mg, 0.159 mmol) then 2-dimethylaminoethyl chloridehydrochloride (15 mg, 0.102 mmol). The resulting mixture was stirred 1 hat 60° C. After cooling to ambient temperature, potassium carbonate wasadded. The resulting mixture was stirred overnight at 60° C. Aftercooling to ambient temperature, reaction was diluted with DCM andpurified directly by silica chromatography (0.5-10% MeOH in DCM with0.1-2% NH₄OH as the gradient eluent) to afford the title compound (14mg, 47% yield). MS (apci) m/z=559.2 (M+H).

Example 316

3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl3-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate.To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 37 mg, 0.076 mmol) in DMF (0.76 mL) was added cesiumcarbonate (27 mg, 0.083 mmol) then tert-butyl3-(bromomethyl)-3-fluoroazetidine-1-carboxylate (41 mg, 0.15 mmol). Theresulting mixture was stirred 3 h at 60° C. After cooling to ambienttemperature, reaction was diluted with EtOAc and washed with water andbrine and the organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo to afford the title compound (Assumedquantitative yield, 51 mg) MS (apci) m/z=675.3 (M+H).

Step 2: Preparation of3-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide.To a solution of tert-butyl3-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(62 mg, 0.092 mmol) in DCM (0.46 mL) was treated with TFA (0.46 mL, 6mmol). The reaction mixture was stirred for 15 min at ambienttemperature, and then concentrated in vacuo. The residue was resuspendedin DCM (3 mL). The solution was passed through two Pl-HCO₃ resins andeluted with additional DCM. The eluent was concentrated in vacuo toafford the title compound (30 mg, 57% yield) MS (apci) m/z=575.2 (M+H).

Step 3: Preparation of3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide.To a solution of3-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(35 mg, 0.061 mmol) in DMA (0.61 mL) was added formaldehyde (8 μL, 0.304mmol) and NaBH(AcO)₃ (116 mg, 0.547 mmol) The resulting reaction mixturewas allowed to stir overnight at room temperature. The reaction wasdirectly purified by C18 reverse phase chromatography (5-75% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was diluted with DCM and passed through aPl-HCO₃ resin and eluted with additional DCM. The eluent wasconcentrated in vacuo. The residue was dissolved in DCM and treated withsaturated NaHCO_(3(aq)) and extracted with 4:1 DCM:IPA. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (7 mg, 19% yield) MS(apci) m/z=589.3 (M+H).

Example 317

3-chloro-N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 36 mg, 0.074 mmol) in DMA (0.74 mL) was added cesiumcarbonate (26 mg, 0.081 mmol) followed by 4-(2-chloroethyl)morpholine(44 mg, 0.295 mmol) was added to the reaction mixture. The resultingmixture was stirred overnight at 60° C. After cooling to ambienttemperature, reaction was diluted with 60:40 ACN:water. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA and then washed with brine. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (9 mg, 20% yield) MS(apci) m/z=601.3 (M+H).

Example 318

3-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 36 mg, 0.074 mmol) in DMF (0.74 mL) was addedpotassium carbonate (31 mg, 0.221 mmol) followed by iodoethane (17 mg,0.111 mmol). The resulting mixture was stirred overnight at 60° C. Aftercooling to ambient temperature, reaction was diluted with 60:40ACN:water. The solution was purified directly by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO_(3(aq)) and extracted with 4:1 DCM:IPA and thenwashed with brine. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (19 mg, 50% yield) MS (apci) m/z=516.2 (M+H).

Example 319

3-chloro-N-(1-(5-(3-cyano-6-(2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 31 mg, 0.063 mmol) in DMA (0.63 mL) was addedpotassium carbonate (10 mg, 0.69 mmol) followed by1-(2-Chloroethyl)-pyrrolidine (25 mg, 0.189 mmol). The resulting mixturewas stirred overnight at 60° C. After cooling to ambient temperature,the reaction mixture was diluted with EtOAc and washed with water. Thewater layer was further extracted using 4:1 DCM:IPA. The organicextracts were separately washed with brine, then combined and dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue wasresuspended with 60:40 ACN:water. The solution was purified directly byC18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA and then washed with brine. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (16 mg, 42% yield) MS (apci) m/z=585.3 (M+H).

Example 320

tert-butyl(2-((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate

To a mixture of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75; 150 mg, 0.307 mmol) and potassium carbonate (47 mg,0.34 mmol) in DMA (3.07 mL) was added 2-(boc-amino)ethyl bromide (138mg, 0.615 mmol). The resulting mixture was stirred overnight at 60° C.After cooling to ambient temperature, additional 2-(boc-amino)ethylbromide (69 mg, 0.307 mmol) was added and reaction stirred for 1 h atambient temperature. Then additional potassium carbonate (42 mg, 0.31mmol) was added and reaction stirred for two overnights at 60° C. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc and washed with water. The organic extracts were washed withbrine, then combined and dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(10-90% EtOAc in hexanes as the gradient eluent) to afford the titlecompound in sufficient purity for the next step. 10 mg of the titlecompound was repurified using C18 reverse phase chromatography (5-95%ACN in water with 0.1% TFA as the gradient eluent) to afford the titlecompound as the TFA salt. The TFA salt was treated with saturatedNaHCO_(3(aq)) and extracted with 4:1 DCM:IPA and then washed with brine.The combined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo to afford the title compound. (169mg, 87% yield) MS (apci) m/z=631.3 (M+H).

Example 321

N-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-chloropicolinamide

To a solution tert-butyl(2-((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate(Example 320, 158 mg, 0.250 mmol) in DCM (2.5 mL) was treated with TFA(2.5 mL, 32 mmol). The reaction mixture was stirred for 10 min atambient temperature, and then concentrated in vacuo. The residue wastreated with saturated NaHCO_(3(aq)) and extracted with 4:1 DCM:IPA andthen washed with brine. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (130 mg, 98% yield) MS (apci) m/z=531.2 (M+H)

Example 322

N-(1-(5-(6-(2-acetamidoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-chloropicolinamide

To a solution ofN-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-chloropicolinamide(Example 321; 27 mg, 0.51 mmol) in DCM (0.5 mL) was added aceticanhydride (5 μL, 0.51 mmol) followed by TEA (14 μL, 0.102 mmol). Thereaction solution was stirred for 1 h at ambient temperature. Thereaction was concentrated in vacuo. The residue was resuspended with60:40 ACN:water. The solution was purified directly by C18 reverse phasechromatography (5-75% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt was treatedwith saturated NaHCO_(3(aq)) and extracted with 4:1 DCM:IPA and thenwashed with brine. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo to afford thetitle compound (20 mg, 67% yield) MS (apci) m/z=573.2 (M+H).

Example 323

3-chloro-N-(1-(5-(3-cyano-6-(2-((2,2-difluoroethyl)amino)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution ofN-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-chloropicolinamide(Example 321, 27 mg, 0.051 mmol) in DMA (0.5 mL) was added potassiumcarbonate (35 mg, 0.254 mmol). The suspension was sparged with argon andstirred for 10 min at ambient temperature. Then 2,2-difluoroethyltrifluoromethanesulfonate (11 mg, 0.51 mmol). The resulting mixture wassparged with argon and stirred 60 h at 60° C. After cooling to ambienttemperature, reaction was diluted with 60:40 ACN:water. The solution waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA and then washed with brine. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (4 mg, 13% yield) MS(apci) m/z=595.2 (M+H).

Example 324

6-ethoxy-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((6-methoxypyridazin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.0 g,49.7 mmol) in DMF (82.8 mL) was added sodium hydride (2.19 g, 54.7mmol). The mixture was stirred at rt for 15 mins, after which3-chloro-6-methoxypyridazine (7.18 g, 49.7 mmol) was added. The reactionmixture was stirred at 90° C. for 24 h. After cooling to ambienttemperature, the reaction mixture was diluted with saturatedNaHCO_(3(aq)) and extracted with EtOAc. The combined organic extractswere washed with water and brine, dried over anhydrous Na₂SO_(4(s)), andconcentrated in vacuo. The residue was purified by silica chromatography(5-50% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 15.4 g, 49.8 mmol) in sufficientpurity for Step 2. MS (apci) m/z=310.1 (M+H).

Step 2: Preparation of 3-methoxy-6-(piperidin-4-yloxy)pyridazine

To a solution of tert-butyl4-((6-methoxypyridazin-3-yl)oxy)piperidine-1-carboxylate (assumed 15.4g, 49.8 mol) in DCM (16 mL) was added TFA (19.2 mL, 250.9 mmol). Thereaction mixture was stirred at rt 15 min, at which time it wasconcentrated in vacuo. The residue was resuspended in 20 mL DCM andpurified by silica chromatography (1-9% MeOH in DCM with 1% NH₄OH as thegradient eluent) to afford the title compound (6.0 g, 28.7 mmol, 57.6%yield over two steps) in sufficient purity for Step 3. MS (apci)m/z=210.1 (M+H).

Step 3: Preparation of6-ethoxy-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.012 g, 0.0425 mmol) in DMSO (0.1 mL) was added3-methoxy-6-(piperidin-4-yloxy)pyridazine (0.0133 g, 0.0638 mmol) andDIEA (37 μL, 0.213 mmol). The reaction mixture was stirred at 110° C.for 24 h. After cooling to ambient temperature, the reaction mixture wasdiluted with DCM and washed with saturated NH₄Cl_((aq)). The combinedaqueous washes were further extracted with DCM, and the combined organicextracts were dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by silica chromatography (0-100% EtOAcin hexanes as the gradient eluent) to afford the title compound (6 mg,0.0127 mmol, 30% yield). MS (apci) m/z=472.2 (M+H).

Example 325

4-(6-(4-benzyl-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 30 mg, 0.106 mmol) in DMA (0.5 mL) was added TEA(0.044 mL, 0.319 mmol) and 4-benzylpiperidin-4-ol (40.7 mg, 0.213 mmol)The reaction mixture was stirred at 90° C. for 24 h. After cooling toambient temperature, the reaction mixture was diluted with DCM andwashed with saturated NH₄Cl_((aq)) then water. The combined aqueouswashes were further extracted with DCM, and the combined organicextracts were dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by silica chromatography (30-100% EtOAcin hexanes as the gradient eluent) to afford the title compound (39 mg,0.0860 mmol, 80.9% yield). MS (apci) m/z=454.2 (M+H).

The compounds in Table RR were prepared using a similar method to thatdescribed for the synthesis of Example 325, replacing4-benzylpiperidin-4-ol with the appropriate piperidine nucleophile.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE RR MS Ex. # Structure Chemical Name m/z 326

6-ethoxy-4-(6-(4-hydroxy- 4-(2-(pyridin-3- yl)ethyl)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 469.15 (M + H)327

6-ethoxy-4-(6-(4-hydroxy- 4-phenylpiperidin-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 440.15 (M + H) 328

6-ethoxy-4-(6-(4-hydroxy- 4-(pyridin-2-yl)piperidin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 441.10 (M + H) 329

6-ethoxy-4-(6-(4-hydroxy- 4-(pyridin-3-yl)piperidin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 441.10 (M + H) 330

6-ethoxy-4-(6-(4-hydroxy- 4-(pyridin-4-yl)piperidin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 441.10 (M + H)

Example 331

6-ethoxy-4-(6-(4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P52, 30 mg, 0.0825 mmol) in 1:1 DCM/THF (0.7 mL) was added6-methylpyridazin-3-ol (18.2 mg, 0.165 mmol) and triphenylphosphane(43.3 mg, 0.165 mmol). The reaction vessel was sparged with argon, atwhich time diisopropyl (E)-diazene-1,2-dicarboxylate (0.0235 ml, 0.165mmol) was added, and the reaction mixture was stirred at rt 24 h. Thereaction mixture was diluted with DCM and washed with water. The aqueousfraction was extracted with DCM, and the combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (50-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (15 mg, 0.0329 mmol, 39.9%yield). MS (apci) m/z=456.2 (M+H).

Example 332

4-(6-(4-((6-chloropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared using a similar method to that describedfor the synthesis of Example 331, replacing 6-methylpyridazin-3-ol with6-chloropyridin-3-ol. MS (apci) m/z=475.2 (M+H).

Example 333

6-ethoxy-4-(6-(4-((6-(2-hydroxyethoxy)pyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of ethane-1,2-diol (9.8 mg, 0.16 mmol) in DMF (0.2 mL) wasadded sodium hydride (60% w/w, 2.3 mg, 0.095 mmol) and stirred at rt for5 min, at which time4-(6-(4-((6-chloropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 332, 15 mg, 0.032 mmol) in an additional 0.3 mL of DMF wasadded. The reaction mixture was stirred at 110° C. for 24 h. Aftercooling to ambient temperature, the reaction mixture was quenched withsaturated NH₄Cl and extracted with DCM. The combined organic extractswere dried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. Theresidue was purified by C-18 reverse phase chromatography (10-90% ACN inwater with 0.1% formic acid as the gradient eluent) to afford the titlecompound (2.2 mg, 0.0044 mmol, 14% yield). MS (apci) m/z=501.25 (M+H).

Example 334

N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-hydroxypropanamide

To a solution of4-(6-(4-benzyl-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P53, 19.5 mg, 0.0430 mmol) was added3-hydroxypropanenitrile (0.5 mL, 0.0430 mmol). The mixture was stirredat rt for 5 min, at which time sulfuric acid (98%, 0.0023 mL, 0.0430mmol) was added dropwise. The reaction mixture was stirred at rt for 24h. The crude mixture was purified by C-18 reverse phase chromatography(0-70% ACN in water as the gradient eluent) to afford the title compound(6 mg, 0.01 mmol, 27% yield). MS (apci) m/z=547.2 (M+H).

Example 335

N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-hydroxy-3-methylbutanamide

The title compound was prepared using a similar method to that describedfor the synthesis of Example 334, replacing 3-hydroxypropanenitrile with3-hydroxy-3-methylbutanenitrile. MS (apci) m/z=553.2 (M+H).

Example 336

4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(100.5 mg, 0.3560 mmol) in DMSO (3 ml) was added(4-benzylpiperidin-4-yl)methanol hydrochloride (151.5 mg, 0.6267 mmol)and cesium carbonate (812.0 mg, 2.492 mmol). The reaction mixture wasstirred at 60° C. for 24 h. After cooling to ambient temperature, thereaction mixture was diluted with DCM and washed with water andsaturated NH₄Cl_((aq)). The combined aqueous layers were extracted withDCM, then the combined organic extracts were dried over anhydrousNa₂SO_(4(s)) and concentrated in vacuo. The residue was purified bysilica chromatography (0-100% EtOAc in hexanes as the gradient eluent)to afford the title compound (118.2 mg, 0.2528 mmol, 71.00% yield). MS(apci) m/z=468.2 (M+H).

Example 337

4-(6-(4-benzyl-4-(methoxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P55, 9.0 mg, 0.019 mmol) in DMF (0.4 mL) was added sodiumhydride (60% w/w, 2.8 mg, 0.070 mmol). This mixture was stirred at rt 1h, at which time methyl iodide (0.021 ml, 0.34 mmol) was added. Thereaction mixture was stirred at rt for 72 h. The reaction mixture wasdiluted with DCM and washed with water. The combined organic extractswere dried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. Theresidue was purified by silica chromatography (0-100% EtOAc in hexanesas the gradient eluent) to afford the title compound (4.0 mg, 0.0083mmol, 43% yield). MS (apci) m/z=482.25 (M+H).

Example 338

2-((4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)methoxy)-N,N-dimethylacetamide

The title compound was prepared using a similar method to that describedfor the synthesis of Example 337, replacing methyl iodide with2-chloro-N,N-dimethylacetamide. MS (apci) m/z=553.2 (M+H).

Example 339

6-ethoxy-4-(6-(4-(hydroxymethyl)-4-(4-methoxybenzyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-formyl-4-(4-methoxybenzyl)piperidine-1-carboxylate

To a sealed 3-neck flask that had been sparged with N₂ was addedtert-butyl 4-formylpiperidine-1-carboxylate (201.8 mg, 0.9462 mmol) inTHF (2 mL). The mixture was cooled to −78° C. and stirred at thistemperature for 10 min, at which time lithium bis(trimethylsilyl)amide(3 mL, 3 mmol) was added dropwise. The reaction mixture was stirred at−78° C. for 40 min then warmed to rt. After 16 h,1-(bromomethyl)-4-methoxybenzene (0.3 mL, 2.058 mmol) was added, and thereaction mixture was stirred an additional 24 h at rt. The reaction wasquenched with water, extracted into EtOAc, and the organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo to affordthe title compound (assumed theoretical yield, 315 mg, 0.946 mmol) insufficient purity for Step 2. MS (apci) m/z=234.2 (M+H−Boc).

Step 2: Preparation of 4-(4-methoxybenzyl)piperidine-4-carbaldehyde

To a solution of tert-butyl4-formyl-4-(4-methoxybenzyl)piperidine-1-carboxylate (assumed 315 mg,0.946 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol). The reactionmixture was stirred at rt 30 min then concentrated in vacuo. The residuewas diluted in DCM and 10% NH₄OH in MeOH and stirred for 15 min. Themixture was concentrated in vacuo to afford the title compound (assumedtheoretical yield, 220.8 mg, 0.9462 mmol) in sufficient purity for Step3. MS (apci) m/z=234.2 (M+H).

Step 3: Preparation of6-ethoxy-4-(6-(4-formyl-4-(4-methoxybenzyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 40.3 mg, 0.143 mmol) in DMSO (0.5 mL) was added4-(4-methoxybenzyl)piperidine-4-carbaldehyde (66.6 mg, 0.286 mmol) andcesium carbonate (465 mg, 1.43 mmol). The reaction mixture was stirredat 60° C. for 16 h. After cooling to ambient temperature, the reactionmixture was diluted with water and extracted with DCM. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)) and purified bysilica chromatography (0-100% EtOAc in hexanes as the gradient eluent)to afford the title compound (assumed theoretical yield, 70.8 mg, 0.143mmol) in sufficient purity for Step 4. MS (apci) m/z=496.2 (M+H).

Step 4: Preparation of6-ethoxy-4-(6-(4-(hydroxymethyl)-4-(4-methoxybenzyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.MeOH (0.5 mL) was added to6-ethoxy-4-(6-(4-formyl-4-(4-methoxybenzyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(assumed 70.8 mg, 0.143 mmol) and stirred at rt 10 min, at which timesodium borohydride (103.5 mg, 2.736 mmol) was added. The reactionmixture was stirred at rt 1.5 h then quenched with water and 2M HCl. ThepH of the mixture was adjusted to 12 with 2M NaOH, and the mixture wasextracted with 4:1 DCM/IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by C-18 reverse phase chromatography (0-70% ACN in water with0.1% TFA). The fractions containing the desired product were free-basedwith saturated NaHCO_(3(aq)) to afford the title compound (1.1 mg,0.00221 mmol, 1.57% yield over four steps). MS (apci) m/z=498.3 (M+H).

Example 340

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution of4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P56, 30 mg, 0.0764 mmol) in DCM (0.005 mL) was added5-fluoro-2-methylbenzoic acid (11.8 mg, 0.0764 mmol), DIEA (13.4 μl,0.0764 mmol), and HATU (29.1 mg, 0.0764 mmol). The reaction mixture wasstirred at rt 24 h then purified by C18 prep HPLC eluting with a 5-95%acetonitrile/water+0.1% TFA gradient then silica chromatography elutingwith (0-100% EtOAc in Hexanes then 0-10% MeOH in EtOAc as the gradienteluent) followed by trituration with 1:3 DCM/MTBE to afford the titlecompound (23.8 mg, 0.045 mmol, 59% yield). MS (apci) m/z=529.2 (M+H).

The compounds in Table SS were prepared using a similar method to thatdescribed for the synthesis of Example 340, replacing5-fluoro-2-methylbenzoic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE SS MS Ex. # Structure Chemical Name m/z 341

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2- yl)-4-(hydroxymethyl)piperidin- 4-yl)-2,6- difluorobenzamide 533.20 (M + H)342

3-chloro-N-(1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4- (hydroxymethyl)piperidin-4-yl)picolinamide 532.20 (M⁺) 343

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2- yl)-4-(hydroxymethyl)piperidin- 4-yl)-3-fluoropicolinamide 516.20 (M + H)

Example 344

(R)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

A solution of tert-butyl(R)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(Intermediate P57, 30 mg, 0.0649 mmol) in DCM (0.1 mL) was treated withTFA (0.124 mL). The reaction mixture was stirred at rt for 3 h before itwas concentrated in vacuo to yield the title product (12 mg, 31% yield).MS (apci) m/z=363.2 (M+H).

Example 345

(R)-4-(6-(3-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(R)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(Intermediate P57, 30 mg, 0.0649 mmol) in formic acid (0.489 mL) wastreated with formaldehyde (0.195 mL, 2.59 mmol). The reaction mixturewas stirred at 90° C. for 24 h. After cooling to ambient temperature,the reaction mixture was quenched with water and extracted with DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by C-18 reverse phasechromatography (10-90% ACN in water+0.1% formic acid as the gradienteluent) to afford the title compound (2.0 mg, 0.00512 mmol, 7.90%yield). MS (apci) m/z=391.25 (M+H).

Example 346

(R)-4-(6-(3-(benzylamino)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of(R)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 344, 10 mg, 0.0276 mmol) in DMA (0.4 mL) was added TEA (0.0115mL, 0.0828 mmol) and (bromomethyl)benzene (0.003 mL, 0.028 mmol). Thereaction mixture was stirred at rt for 24 h. The reaction mixture wasquenched with saturated NH₄Cl_((aq)) and extracted into DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(0-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (3.9 mg, 31% yield). MS (apci) m/z=453.2 (M+H).

Example 347

6-ethoxy-4-(6-((3R,4R)-4-methyl-3-(methylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-3-yl)(methyl)carbamate.To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 60 mg, 0.213 mmol) in DMSO (0.4 mL) was addedpotassium carbonate (147 mg, 1.06 mmol) and tert-butylmethyl((3R,4R)-4-methylpiperidin-3-yl)carbamate (146 mg, 0.638 mmol).The reaction mixture was stirred at 110° C. for 24 h. After cooling toambient temperature, the reaction mixture was quenched with saturatedNH₄Cl_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (72.5 mg, 0.148 mmol,69.5% yield) in sufficient purity for step 2. MS (apci) m/z=491.3 (M+H).

Step 2: Preparation of6-ethoxy-4-(6-((3R,4R)-4-methyl-3-(methylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-3-yl)(methyl)carbamate(0.020 g, 0.0408 mmol) in DCM (0.2 mL) was added 5M HCl in IPA (0.204mL, 1.02 mmol). The reaction mixture was stirred at rt for 24 h, atwhich time it was quenched in water and adjusted to pH 10 by addition of2M NaOH_((aq)). The solution was extracted with DCM, and the combinedorganic extracts were concentrated in vacuo to afford the title compound(0.0145 g, 0.0371 mmol, 91.1% yield). MS (apci) m/z=391.2 (M+H).

Example 348

4-(6-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl((3R,5S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate(Intermediate P62, 0.020 g, 0.038 mmol) in DCM (0.2 mL) was treated with5M HCl in IPA (0.19 mL, 1.1 mmol). The reaction was stirred at rt 6 h.The reaction mixture was concentrated in vacuo, and the residue waspurified by silica chromatography (0-30% [9:1 MeOH/NH₄OH] in EtOAc) toafford the title compound (0.0073 g, 0.017 mmol, 45% yield). MS (apci)m/z=431.2 (M+H).

Example 349

6-ethoxy-4-(6-((3R,5S)-3-(methylamino)-5-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3R,5S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)(methyl)carbamate.A solution of tert-butyl((3R,5S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate(Intermediate P62, 0.020 g, 0.038 mmol) in DMA (0.5 mL) was cooled to 0°C. then treated with sodium hydride (60% w/w, 0.0090 g, 0.11 mmol). Thereaction mixture was warmed to rt and stirred for 20 min, at which timeiodomethane (0.016 g, 0.11 mmol) was added and the reaction mixturestirred at rt an additional 24 h. The reaction mixture was quenched withsaturated NH₄Cl_((aq)) and extracted into DCM. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by silica chromatography (0-100% EtOAcin hexanes as the gradient eluent) to afford the title compound (0.010g, 0.018 mmol, 49% yield) in sufficient purity for step 2. MS (apci)m/z=545.25 (M+H).

Step 2: Preparation of6-ethoxy-4-(6-((3R,5S)-3-(methylamino)-5-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. A solution of tert-butyl((3R,5S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)(methyl)carbamate(0.010 g, 0.018 mmol) in DCM (0.2 mL) was treated with 5M HCl in IPA(0.2 ml, 0.018 mmol). The reaction was stirred at rt 6 h. The reactionmixture was concentrated in vacuo, and the residue was purified bysilica chromatography (0-30% [9:1 MeOH/NH₄OH] in EtOAc) to afford thetitle compound (0.0045 g, 0.010 mmol, 55% yield). MS (apci) m/z=445.2(M+H).

Example 350

4-(6-((3S,4R)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of4-(6-((3S,4R)-3-azido-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P58, 0.050 g, 0.128 mmol) in 1:1 DCM/THF (0.7 mL) wasadded pyridin-2-ol (0.0244 g, 0.256 mmol) and triphenylphosphane (0.0672g, 0.256 mmol). The reaction mixture was sparged with argon, diisopropyl(E)-diazene-1,2-dicarboxylate (0.0350 mL, 0.256 mmol) was added. Thereaction mixture was stirred at rt for 24 h. It was quenched with waterand extracted into DCM. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (20-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.014 g, 0.0299 mmol,23.4% yield) in sufficient purity for step 2. MS (apci) m/z=468.1 (M+H).

Step 2: Preparation of4-(6-((3S,4R)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3S,4R)-3-azido-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(0.013 g, 0.028 mmol) in 1:1 MeOH/EtOAc (2 mL) was added 10% palladiumon carbon (0.33 mg, 0.0028 mmol). The reaction mixture was sparged withH₂ and stirred at rt for 24 h. The solids were removed by filtration,and the filtrate was concentrated in vacuo. The residue was purified bysilica chromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc as the gradienteluent) to afford the title compound (7 mg, 56% yield). MS (apci)m/z=442.2 (M+H).

Example 351

4-(6-((3S,4S)-3-amino-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-((3S,4S)-3-azido-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P58, 0.027 g, 0.069 mmol) in DMA (0.5 mL) was addedpotassium carbonate (0.029 g, 0.21 mmol) and 1-iodopropane (0.021 ml,0.21 mmol). The reaction mixture was stirred at 85° C. for 48 h. Aftercooling to ambient temperature, the reaction was quenched with water andextracted into DCM. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 0.030 g, 0.069 mmol) in sufficient purity for step 2. MS (apci)m/z=433.2 (M+H).

Step 2: Preparation of4-(6-((3S,4S)-3-amino-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3S,4S)-3-azido-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(0.022 g, 0.051 mmol) in EtOAc (5 mL) was added 10% palladium on carbon(0.012 g, 0.010 mmol). The reaction mixture was sparged with H₂ andstirred at rt for 24 h. The solids were removed by filtration, and thefiltrate was concentrated in vacuo. The residue was purified by silicachromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc as the gradient eluent)to afford the title compound (0.0026 g, 0.0064 mmol, 13% yield over twosteps). MS (apci) m/z=407.2 (M+H).

Example 352

4-(6-((3S,4S)-3-amino-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-((3S,4S)-3-azido-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P58, 0.027 g, 0.069 mmol) in DMA (0.5 mL) was addedpotassium carbonate (0.029 g, 0.21 mmol) and 1-bromo-2-methylpropane(0.024 ml, 0.21 mmol). The reaction mixture was stirred at 85° C. for120 h. It was quenched with saturated NH₄C_((aq)) and extracted intoDCM. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)) and concentrated in vacuo. The residue was purified bysilica chromatography (0-100% EtOAc in hexanes as the gradient eluent)to afford the title compound (assumed theoretical yield, 0.031 g, 0.069mmol) in sufficient purity for step 2. MS (apci) m/z=447.1 (M+H).

Step 2: Preparation of4-(6-((3S,4S)-3-amino-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3S,4S)-3-azido-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitril e (0.015 g, 0.034 mmol) in EtOAc (5 mL) was added 10% palladiumon carbon (0.012 g, 0.010 mmol). The reaction mixture was sparged withH₂ and stirred at rt for 24 h. The solids were removed by filtration,and the filtrate was concentrated in vacuo. The residue was purified bysilica chromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc as the gradienteluent) to afford the title compound (0.0033 g, 0.0078 mmol, 23% yieldover two steps). MS (apci) m/z=421.25 (M+H).

Example 353

4-(6-((3S,4S)-3-amino-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of4-(6-((3S,4S)-3-azido-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P58, 0.040 g, 0.10 mmol) in DMA (0.7 mL) was added cesiumcarbonate (0.17 g, 0.51 mmol) and 2-(2-bromoethoxy)propane (0.086 g,0.51 mmol). The reaction mixture was stirred at 90° C. for 96 h. It wasquenched with saturated NH₄C_((aq)) and extracted into DCM. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)) and concentratedin vacuo. The residue was purified by silica chromatography (0-100%EtOAc in hexanes as the gradient eluent) to afford the title compound(assumed theoretical yield, 0.048 g, 0.10 mmol) in sufficient purity forstep 2.

Step 2: Preparation of4-(6-((3S,4S)-3-amino-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3S,4S)-3-azido-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(0.048 g, 0.010 mmol) in EtOAc (2 mL) was added 10% palladium on carbon(0.010 g, 0.010 mmol). The reaction mixture was sparged with H₂ andstirred at rt for 24 h. The solids were removed by filtration, and thefiltrate was concentrated in vacuo. The residue was purified by silicachromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc as the gradient eluent)to afford the title compound (8 mg, 0.017 mmol, 16% yield over twosteps). MS (apci) m/z=452.3 (M+H).

Example 354

4-(6-((3R,4S)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of4-(6-((3R,4S)-3-azido-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P59, 0.050 g, 0.128 mmol) in 1:1 DCM/THF (0.7 mL) wasadded pyridin-2-ol (0.0244 g, 0.256 mmol) and triphenylphosphane (0.0672g, 0.256 mmol). The reaction mixture was sparged with argon, diisopropyl(E)-diazene-1,2-dicarboxylate (0.0350 mL, 0.256 mmol) was added. Thereaction mixture was stirred at rt for 24 h. It was quenched with waterand extracted into DCM. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (20-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.025 g, 0.0535 mmol,41.8% yield) in sufficient purity for step 2. MS (apci) m/z=468.1 (M+H).

Step 2: Preparation of4-(6-((3R,4S)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3R,4S)-3-azido-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(0.022 g, 0.0471 mmol) in 1:1 MeOH/EtOAc (2 mL) was added 10% palladiumon carbon (0.56 mg, 0.0047 mmol). The reaction mixture was sparged withH₂ and stirred at rt for 24 h. The solids were removed by vacuumfiltration, and the filtrate was concentrated in vacuo. The residue waspurified by silica chromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc asthe gradient eluent) to afford the title compound (13 mg, 0.0297 mmol,63.1% yield). MS (apci) m/z=442.2 (M+H).

Example 355

4-(6-((3R,4R)-3-amino-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-((3R,4R)-3-azido-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P59, 0.025 g, 0.064 mmol) in DMA (0.5 mL) was addedpotassium carbonate (0.027 g, 0.19 mmol) and 1-bromo-2-methylpropane(0.022 ml, 0.19 mmol). The reaction mixture was stirred at 85° C. for120 h. It was quenched with saturated NH₄Cl_((aq)) and extracted intoDCM. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)) and concentrated in vacuo. The residue was purified bysilica chromatography (0-100% EtOAc in hexanes as the gradient eluent)to afford the title compound (assumed theoretical yield, 0.029 g, 0.064mmol) in sufficient purity for step 2. MS (apci) m/z=447.2 (M+H).

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3R,4R)-3-azido-4-isobutoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitril e (0.014 g, 0.032 mmol) in EtOAc (5 mL) was added 10% palladiumon carbon (0.012 g, 0.010 mmol). The reaction mixture was sparged withH₂ and stirred at rt for 24 h. The solids were removed by filtration,and the filtrate was concentrated in vacuo. The residue was purified bysilica chromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc as the gradienteluent) to afford the title compound (1 mg, 0.0024 mmol, 7.3% yield overtwo steps). MS (apci) m/z=421.3 (M+H).

Example 356

4-(6-((3R,4R)-3-amino-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-((3R,4R)-3-azido-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P59, 0.025 g, 0.064 mmol) in DMA (0.5 mL) was addedpotassium carbonate (0.027 g, 0.19 mmol) and 1-iodopropane (0.019 mL,0.19 mmol). The reaction mixture was stirred at 85° C. for 48 h. Aftercooling to ambient temperature, the reaction was quenched with water andextracted into DCM. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 0.028 g, 0.064 mmol) in sufficient purity for step 2. MS (apci)m/z=433.2 (M+H).

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-((3R,4R)-3-azido-4-propoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(0.017 g, 0.039 mmol) in EtOAc (5 mL) was added 10% palladium on carbon(0.0093 g, 0.0079 mmol). The reaction mixture was sparged with H₂ andstirred at rt for 24 h. The solids were removed by vacuum filtration,and the filtrate was concentrated in vacuo. The residue was purified bysilica chromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc as the gradienteluent) to afford the title compound (0.0026 g, 0.0064 mmol, 16% yieldover two steps). MS (apci) m/z=407.2 (M+H).

Example 357

4-(6-((3R,4R)-3-amino-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of4-(6-((3R,4R)-3-azido-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3R,4R)-3-azido-4-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P59, 0.025 g, 0.064 mmol) in DMA (0.5 mL) was added cesiumcarbonate (0.10 g, 0.32 mmol) and 2-(2-bromoethoxy)propane (0.053 g,0.32 mmol). The reaction mixture was stirred at 90° C. for 96 h. It wasquenched with saturated NH₄C_((aq)) and extracted into DCM. The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)) and concentratedin vacuo. The residue was purified by silica chromatography (0-100%EtOAc in hexanes as the gradient eluent) to afford the title compound(assumed theoretical yield, 0.031 g, 0.064 mmol) in sufficient purityfor step 2.

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.To a solution of4-(6-((3R,4R)-3-azido-4-(2-isopropoxyethoxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(0.031 g, 0.064 mmol) in EtOAc (2 mL) was added 10% palladium on carbon(0.010 g, 0.010 mmol). The reaction mixture was sparged with H₂ andstirred at rt for 24 h. The solids were removed by filtration, and thefiltrate was concentrated in vacuo. The residue was purified by silicachromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAc as the gradient eluent)to afford the title compound (0.0043 g, 0.0095 mmol, 15% yield over twosteps). MS (apci) m/z=452.3 (M+H).

Example 358

4-(6-((3R,4R)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate.To a solution of tert-butyl((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P60, 0.030 g, 0.0646 mmol) in 1:1 DCM/THF (0.75 mL) wasadded pyridin-2-ol (0.0123 g, 0.129 mmol) and triphenylphosphane (0.0339g, 0.129 mmol). The reaction mixture was sparged with argon, anddiisopropyl (E)-diazene-1,2-dicarboxylate (0.0176 mL, 0.129 mmol) wasadded. The reaction mixture was stirred at rt for 24 h. It was quenchedwith water and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (20-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 0.035 g, 0.0646 mmol) in sufficient purity for step 2.

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate(0.035 g, 0.0646 mmol) in DCM (2 mL) was treated with 6M HCl in IPA (2mL) and stirred at rt for 24 h. The reaction mixture was concentrated invacuo, and the residue was taken up in water. 2M NaOH was added andextracted with DCM. The combined organic extracts were passed through aphase separator frit then purified by silica chromatography (0-40% [9:1MeOH/NH₄OH] in EtOAc as the gradient eluent) to afford the titlecompound (0.0073 g, 0.0165 mmol, 25.6% yield over two steps). MS (apci)m/z=442.2 (M+H).

Example 359

4-(6-((3R,4R)-3-amino-4-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate.To a solution of tert-butyl((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P60, 0.030 g, 0.0646 mmol) in 1:1 DCM/THF (0.75 mL) wasadded 5-methoxypyridin-2-ol (0.0162 g, 0.129 mmol) andtriphenylphosphane (0.0339 g, 0.129 mmol). The reaction mixture wassparged with argon, and diisopropyl (E)-diazene-1,2-dicarboxylate(0.0176 mL, 0.129 mmol) was added. The reaction mixture was stirred atrt for 24 h. It was quenched with water and extracted into DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(20-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 0.037 g, 0.0646 mmol) in sufficientpurity for step 2.

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate(0.037 g, 0.0646) in DCM (2 mL) was treated with 6M HCl in IPA (2 mL)and stirred at rt for 24 h. The reaction mixture was concentrated invacuo, and the residue was taken up in water. 2M NaOH was added andextracted with DCM. The combined organic extracts were passed through aphase separator frit then purified by silica chromatography (0-40% [9:1MeOH/NH₄OH] in EtOAc as the gradient eluent) to afford the titlecompound (0.0065 g, 0.0138 mmol, 21.3% yield over two steps). MS (apci)m/z=472.2 (M+H).

Example 360

4-(6-((3R,4R)-3-amino-4-((6-chloropyridazin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3R,4R)-4-((6-chloropyridazin-3-yl)oxy)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate.To a solution of tert-butyl((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P60, 0.030 g, 0.0646 mmol) in 1:1 DCM/THF (0.7 mL) wasadded 6-chloropyridazin-3-ol (0.0169 g, 0.129 mmol) andtriphenylphosphane (0.0339 g, 0.129 mmol). The reaction mixture wassparged with argon, and diisopropyl (E)-diazene-1,2-dicarboxylate(0.0176 mL, 0.129 mmol) was added. The reaction mixture was stirred atrt for 24 h. It was quenched with water and extracted into DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(20-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 0.031 g, 0.0646 mmol) in sufficientpurity for step 2.

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-((6-chloropyridazin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl((3R,4R)-4-((6-chloropyridazin-3-yl)oxy)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(0.031 g, 0.0646) in DCM (2 mL) was treated with 6M HCl in IPA (2 mL)and stirred at rt for 24 h. The reaction mixture was concentrated invacuo, and the residue was taken up in water. 2M NaOH was added andextracted with DCM. The combined organic extracts were passed through aphase separator frit then purified by silica chromatography (0-40% [9:1MeOH/NH₄OH] in EtOAc as the gradient eluent) to afford the titlecompound (0.013 g, 0.0273 mmol, 42.2% yield over two steps). MS (apci)m/z=477.1 (M+H).

Example 361

4-(6-((3R,4R)-3-amino-4-((5-fluoro-6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((5-fluoro-6-methoxypyridin-3-yl)oxy)pyrrolidin-3-yl)carbamate.To a solution of tert-butyl((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P60, 0.030 g, 0.0646 mmol) in 1:1 DCM/THF (0.7 mL) wasadded 5-fluoro-6-methoxypyridin-3-ol (0.0185 g, 0.129 mmol) andtriphenylphosphane (0.0339 g, 0.129 mmol). The reaction mixture wassparged with argon, and diisopropyl (E)-diazene-1,2-dicarboxylate(0.0176 mL, 0.129 mmol) was added. The reaction mixture was stirred atrt for 24 h. It was quenched with water and extracted into DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(20-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 0.038 g, 0.0646 mmol) in sufficientpurity for step 2.

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-((5-fluoro-6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((5-fluoro-6-methoxypyridin-3-yl)oxy)pyrrolidin-3-yl)carbamate(0.038 g, 0.0646) in DCM (2 mL) was treated with 6M HCl in IPA (2 mL)and stirred at rt for 24 h. The reaction mixture was concentrated invacuo, and the residue was taken up in water. 2M NaOH was added andextracted with DCM. The combined organic extracts were passed through aphase separator frit then purified by silica chromatography (0-40% [9:1MeOH/NH₄OH] in EtOAc as the gradient eluent) to afford the titlecompound (0.0014 g, 0.00286 mmol, 4.43% yield over two steps). MS (apci)m/z=490.2 (M+H).

Example 362

4-(6-((3S,4S)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate.To a solution of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P61, 0.030 g, 0.0646 mmol) in 1:1 DCM/THF (0.75 mL) wasadded pyridin-2-ol (0.0123 g, 0.129 mmol) and triphenylphosphane (0.0339g, 0.129 mmol). The reaction mixture was sparged with argon, anddiisopropyl (E)-diazene-1,2-dicarboxylate (0.0176 mL, 0.129 mmol) wasadded. The reaction mixture was stirred at rt for 24 h. It was quenchedwith water and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (20-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 0.035 g, 0.0646 mmol) in sufficient purity for step 2. MS (apci)m/z=542.3 (M+H).

Step 2: Preparation of4-(6-((3S,4S)-3-amino-4-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate(0.035 g, 0.0646 mmol) in DCM (2 mL) was treated with 6M HCl in IPA (2mL) and stirred at rt for 24 h. The reaction mixture was concentrated invacuo, and the residue was taken up in water. 2M NaOH was added andextracted with DCM. The combined organic extracts were passed through aphase separator frit then purified by silica chromatography (0-40% [9:1MeOH/NH₄OH] in EtOAc as the gradient eluent) to afford the titlecompound (0.0101 g, 0.0229 mmol, 35.4% yield over two steps). MS (apci)m/z=442.2 (M+H).

Example 363

4-(6-((3S,4S)-3-amino-4-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate.To a solution of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P61, 0.030 g, 0.0646 mmol) in 1:1 DCM/THF (0.75 mL) wasadded 5-methoxypyridin-2-ol (0.0162 g, 0.129 mmol) andtriphenylphosphane (0.0339 g, 0.129 mmol). The reaction mixture wassparged with argon, and diisopropyl (E)-diazene-1,2-dicarboxylate(0.0176 mL, 0.129 mmol) was added. The reaction mixture was stirred atrt for 48 h. It was quenched with water and extracted into DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(20-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 0.037 g, 0.0646 mmol) in sufficientpurity for step 2. MS (apci) m/z=572.3 (M+H).

Step 2: Preparation of4-(6-((3S,4S)-3-amino-4-((6-methoxypyridin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate(0.037 g, 0.0646) in DCM (2 mL) was treated with 6M HCl in IPA (2 mL)and stirred at rt for 24 h. The reaction mixture was concentrated invacuo, and the residue was taken up in water. 2M NaOH was added andextracted with DCM. The combined organic extracts were passed through aphase separator frit then purified by silica chromatography (0-40% [9:1MeOH/NH₄OH] in EtOAc as the gradient eluent) to afford the titlecompound (0.0112 g, 0.0238 mmol, 36.8% yield over two steps). MS (apci)m/z=472.2 (M+H).

Example 364

4-(6-((3S,4S)-3-amino-4-((6-chloropyridazin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl((3S,4S)-4-((6-chloropyridazin-3-yl)oxy)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate.To a solution of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P61, 0.030 g, 0.0646 mmol) in 1:1 DCM/THF (0.7 mL) wasadded 6-chloropyridazin-3-ol (0.0169 g, 0.129 mmol) andtriphenylphosphine (0.0339 g, 0.129 mmol). The reaction mixture wassparged with argon, and diisopropyl (E)-diazene-1,2-dicarboxylate(0.0176 mL, 0.129 mmol) was added. The reaction mixture was stirred atrt for 24 h. It was quenched with water and extracted into DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(20-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (assumed theoretical yield, 0.031 g, 0.0646 mmol) in sufficientpurity for step 2. MS (apci) m/z=577.2 (M+H).

Step 2: Preparation of4-(6-((3S,4S)-3-amino-4-((6-chloropyridazin-3-yl)oxy)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile.A solution of tert-butyl((3S,4S)-4-((6-chloropyridazin-3-yl)oxy)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(0.031 g, 0.0646) in DCM (2 mL) was treated with 6M HCl in IPA (2 mL)and stirred at rt for 24 h. The reaction mixture was concentrated invacuo, and the residue was taken up in water. 2M NaOH was added andextracted with DCM. The combined organic extracts were passed through aphase separator frit then purified by silica chromatography (0-40% [9:1MeOH/NH₄OH] in EtOAc as the gradient eluent) to afford the titlecompound (0.0096 g, 0.0201 mmol, 31.2% yield over two steps). MS (apci)m/z=477.2 (M+H).

Example 365

(R)-4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(R)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.025 g, 0.0886 mmol) in DMSO (0.5 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.0771 ml, 0.443 mmol) and tert-butyl(R)-pyrrolidin-3-ylcarbamate (0.0330 g, 0.177 mmol). The reactionmixture was stirred 100° C. for 24 h. After cooling to ambienttemperature, the reaction mixture was quenched with saturatedNH₄C_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (40-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 0.040 g, 0.0886 mmol) in sufficient purity for step 2. MS (apci)m/z=449.2 (M+H).

Step 2: Preparation of(R)-4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(R)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(0.040 g, 0.0886 mmol) in DCM (1.5 mL) was treated with 5M HCl in IPA(1.5 mL) and stirred at rt for 2 h. The reaction mixture wasconcentrated in vacuo, and the residue was taken up in DCM. 2M NaOH wasadded and extracted with DCM. The combined organic extracts were passedthrough a phase separator frit then concentrated in vacuo to afford thetitle compound (0.0227 g, 0.0652 mmol, 73.6% yield over two steps). MS(apci) m/z=349.2 (M+H).

Example 366

(S)-4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.025 g, 0.0886 mmol) in DMSO (0.5 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.0771 ml, 0.443 mmol) and tert-butyl(S)-pyrrolidin-3-ylcarbamate (0.0396 g, 0.213 mmol). The reactionmixture was stirred 100° C. for 24 h. After cooling to ambienttemperature, the reaction mixture was quenched with saturatedNH₄C_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (40-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (assumed theoreticalyield, 0.040 g, 0.0886 mmol) in sufficient purity for step 2. MS (apci)m/z=449.2 (M+H).

Step 2: Preparation of(S)-4-(6-(3-aminopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(0.040 g, 0.0886 mmol) in DCM (1.5 mL) was treated with 5M HCl in IPA(1.5 mL) and stirred at rt for 2 h. The reaction mixture wasconcentrated in vacuo, and the residue was taken up in DCM. 2M NaOH wasadded and extracted with DCM. The combined organic extracts were passedthrough a phase separator frit then concentrated in vacuo to afford thetitle compound (0.0236 g, 0.0677 mmol, 63.7% yield over two steps). MS(apci) m/z=349.1 (M+H).

Example 367

4-(6-((3R,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.050 g, 0.18 mmol) in DMSO (0.35 mL) was added cesiumcarbonate (0.23 g, 0.71 mmol) and tert-butyl((3R,5R)-5-(trifluoromethyl)piperidin-3-yl)carbamate (0.052 g, 0.19mmol). The reaction mixture was stirred 105° C. for 24 h. After coolingto ambient temperature, the reaction mixture was quenched with saturatedNH₄Cl_((aq)) and extracted into DCM. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (0-40% [9:1 MeOH/NH₄OH] in EtOAcas the gradient eluent) followed by purification by preparative HPLC(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The finalproduct fractions were washed with 2M NaOH and extracted with DCM. Thecombined organic extracts were passed through a phase separator frit andconcentrated in vacuo to afford the title compound (0.0085 g, 0.020mmol, 11% yield). MS (apci) m/z=431.2 (M+H).

Example 368

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-phenylpiperidine-4-carboxamideStep 1: Preparation of tert-butyl4-methyl-4-(phenylcarbamoyl)piperidine-1-carboxylate

A solution of 1-Boc-4-methyl-piperidine-4-carboxylic acid (717.3 mg,2.948 mmol) and HATU (1345 mg, 3.538 mmol) in DCM (30 mL) was treatedwith DIEA (1.027 mL, 5.896 mmol) and aniline (0.2958 mL, 3.243 mmol).The reaction mixture was stirred at rt for 60 h, then concentrated invacuo. The residue was purified by silica chromatography (5-70% EtOAc inhexanes as the gradient eluent) to afford the title compound (assumedtheoretical yield, 938.6 mg, 2.948 mmol) in sufficient purity for step2. MS (apci) m/z=219.2 (M+H−Boc).

Step 2: Preparation of 4-methyl-N-phenylpiperidine-4-carboxamide

A solution of tert-butyl4-methyl-4-(phenylcarbamoyl)piperidine-1-carboxylate (938.6 mg, 2.948mmol) in DCM (2 mL) was treated with TFA (2 mL, 26 mmol) and stirred atrt for 16 h. The reaction mixture was concentrated in vacuo. The residuewas diluted with saturated NaHCO_(3(aq)) and extracted with 4:1 DCM/IPA.The combined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo to afford the title compound (240.9 mg, 1.104mmol, 37% yield over two steps) in sufficient purity for step 3. MS(apci) m/z=219.2 (M+H).

Step 3: Preparation of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-phenylpiperidine-4-carboxamide

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.030 g, 0.108 mmol) in DMA (0.5 mL) was added TEA(0.073 mL, 0.538 mmol) and 4-methyl-N-phenylpiperidine-4-carboxamide(0.0705 g, 0.323 mmol). The reaction mixture was stirred 80° C. for 20h. After cooling to ambient temperature, the reaction mixture wasquenched with water and extracted into EtOAc. The combined organicextracts were washed with water and saturated NaCl_((aq)), then driedover anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by C-18 reverse phase chromatography (5-95% ACN in water [+0.1%TFA] as the gradient eluent). The fractions containing the desiredproduct were washed with saturated NaHCO_(3(aq)) and extracted with 4:1DCM/IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)) and concentrated in vacuo to afford the title compound(0.0227 g, 0.0472 mmol, 44% yield). MS (apci) m/z=481.2 (M+H).

Example 369

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-phenylpiperidine-4-carboxamide

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 20.8 mg, 0.0737 mmol) in DMA (0.3 mL) was added TEA(0.0502 mL, 0.368 mmol) and 4-ethyl-N-phenylpiperidine-4-carboxamide(Intermediate R15, 51.4 mg, 0.221 mmol). The reaction mixture wasstirred 90° C. for 16 h. After cooling to ambient temperature, thereaction mixture was quenched with water and extracted into EtOAc. Thecombined organic extracts were washed with water and saturatedNaCl_((aq)), then dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by C-18 reverse phase chromatography(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were washed with saturated NaHCO_(3(aq))and extracted with 4:1 DCM/IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (36.4 mg, 0.0166 mmol,22.5% yield). MS (apci) m/z=495.3 (M+H).

Example 370

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-isobutylpiperidine-4-carboxamide

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 21.4 mg, 0.0758 mmol) in DMA (0.25 mL) was added TEA(0.0517 mL, 0.379 mmol) and 4-ethyl-N-isobutylpiperidine-4-carboxamide(Intermediate R16, 48.3 mg, 0.227 mmol). The reaction mixture wasstirred 90° C. for 14 h. After cooling to ambient temperature, thereaction mixture was quenched with water and extracted into EtOAc. Thecombined organic extracts were washed with water and saturatedNaCl_((aq)), then dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by C-18 reverse phase chromatography(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were washed with saturated NaHCO_(3(aq))and extracted with 4:1 DCM/IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (0-30% MeOH [+2% NH₄OH] in DCM as thegradient eluent) to afford the title compound (25.6 mg, 0.0539 mmol,71.1% yield). MS (apci) m/z=475.3 (M+H).

Example 371

6-ethoxy-4-(6-(4-(isobutylsulfonyl)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of 6-benzyl-1-oxa-6-azaspiro[2.5]octane

A solution of sodium hydride (60% w/w, 4.07 g, 102 mmol) in DMSO (200mL) was treated with trimethylsulfoxonium iodide (22.4 g, 102 mmol)portionwise at rt over the course of 30 min. This mixture was stirred atrt 1 h then treated with 1-benzyl-4-piperidone (14.0 mL, 78.2 mmol). Thereaction mixture was stirred at 60° C. for 16 h. After cooling toambient temperature, the reaction mixture was quenched with water andextracted into EtOAc. The combined organic extracts were washed withwater and saturated NaCl(aq), then dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(5-95% EtOAc [+2% TEA] in DCM as the gradient eluent) to afford thetitle compound (6.5 g, 32.0 mmol, 40.9% yield) in sufficient purity forstep 2.

Step 2: Preparation of 6-benzyl-1-thia-6-azaspiro[2.5]octane

To a solution of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (6.50 g, 32.0mmol) in MeOH (130 mL) was added thiourea (2.68 g, 35.2 mmol). Thereaction mixture was stirred at 40° C. for 16 h. After cooling toambient temperature, the reaction mixture was diluted with EtOAc andwashed with water and saturated NaCl_((aq)) The organic extracts weredried over anhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residuewas purified by silica chromatography (5-75% EtOAc [+2% TEA] in DCM asthe gradient eluent) to afford the title compound (4.84 g, 22.1 mmol,69% yield) in sufficient purity for step 3.

Step 3: Preparation of 1-benzyl-4-methylpiperidine-4-thiol

A solution of 6-benzyl-1-thia-6-azaspiro[2.5]octane (4.84 g, 22.1 mmol)in THF (110 mL) was sparged with N₂ and cooled to 0° C. To this solutionwas added lithium aluminum hydride (33.1 mL, 33.1 mmol), and the mixturewas stirred at 0° C. for 1 h. The reaction mixture was treated withdropwise addition of water and 1M NaOH. The reaction mixture wasextracted with DCM, and the combined organic extracts were washed withwater then dried over anhydrous Na₂SO_(4(s)) and concentrated in vacuoto afford the title compound (2.22 g, 10.0 mmol, 45.5% yield) insufficient purity for step 4.

Step 4: Preparation of 1-benzyl-4-(isobutylthio)-4-methylpiperidine

A solution of 1-benzyl-4-methylpiperidine-4-thiol (1.36 g, 6.144 mmol)in DMF (20 mL) was treated with potassium carbonate (2.547 g, 18.43mmol) and 1-bromo-2-methylpropane (0.8017 mL, 7.373 mmol). The reactionmixture was stirred at 60° C. for 16 h. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc and washed withwater and saturated NaCl_((aq)) The organic extracts were dried overanhydrous Na₂SO_(4(s)) and concentrated in vacuo. The residue waspurified by silica chromatography (5-95% EtOAc [+2% TEA] in DCM as thegradient eluent). The fractions containing the desired product werecombined and concentrated in vacuo, and the residue was purified by C-18reverse phase chromatography (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werecombined and washed with saturated NaHCO_(3(aq)) and extracted into 4:1DCM/IPA. The combined organic extracts were dried over anhydrousNa₂SO_(4(s)) and concentrated in vacuo to afford the title compound(281.3 mg, 1.014 mmol, 16.5% yield) in sufficient purity for step 5.

Step 5: Preparation of 1-benzyl-4-(isobutylsulfonyl)-4-methylpiperidine

A solution of 1-benzyl-4-(isobutylthio)-4-methylpiperidine (10.138 mL,1.014 mmol) in DCM (10 mL) was treated with 3-chloroperoxybenzoic acid(681.6 mg, 3.041 mmol). The reaction mixture was stirred at rt for 16 h.The reaction mixture was diluted with DCM and washed with 10%Na₂CO_(3(aq)). The organic extract was dried over anhydrous Na₂SO_(4(s))and concentrated in vacuo. The residue was purified by C-18 reversephase chromatography (5-95% ACN in water [+0.1% TFA] as the gradienteluent). The fractions containing the desired product were combined andwashed with saturated NaHCO_(3(aq)) and extracted into 4:1 DCM/IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo to afford the title compound (206 mg, 0.6657 mmol,66.5% yield) in sufficient purity for step 6.

Step 6: Preparation of 4-(isobutylsulfonyl)-4-methylpiperidine

A solution of 1-benzyl-4-(isobutylsulfonyl)-4-methylpiperidine (206.0mg, 0.666 mmol) in EtOH (6.7 mL) was treated with palladium on carbon(5%, 70.8 mg, 0.0333 mmol). The reaction mixture was sparged with N₂then H₂, and was stirred at rt under an H₂ atmosphere for 16 h. Thesolids were removed by vacuum filtration, and the filtrate wasconcentrated in vacuo to afford the title compound (144.6 mg, 0.659mmol, 99% yield) in sufficient purity for step 7.

Step 7: Preparation of6-ethoxy-4-(6-(4-(isobutylsulfonyl)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 118.2 mg, 0.4187 mmol) in DMSO (4.2 mL) was added4-(isobutylsulfonyl)-4-methylpiperidine (137.8 mg, 0.6281 mmol) and DIEA(0.1459 mL, 0.8375 mmol). The reaction mixture was stirred at 90° C. for16 h. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc and washed with water and saturated NaCl_((aq)) Theorganic extracts were dried over anhydrous Na₂SO_(4(s)) and concentratedin vacuo. The residue was purified by C-18 reverse phase chromatography(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were combined and washed with saturatedNaHCO_(3(aq)) and extracted into 4:1 DCM/IPA. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo to afford the title compound (72.5 mg, 0.1505 mmol, 36% yield). MS(apci) m/z=482.2 (M+H).

Example 372

N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)acetamideStep 1: Preparation of N-(4-benzylpiperidin-4-yl)acetamide

A solution of 4-benzylpiperidin-4-ol (0.100 g, 0.523 mmol) in ACN (0.5mL) was cooled to 0° C. and then treated with dropwise addition ofsulfuric acid (98%, 0.418 mL, 7.84 mmol). The reaction mixture waswarmed to rt and stirred at the same temperature for 24 h. The reactionmixture was cooled to 0° C. and treated with slow addition of 2M NaOHuntil basic. The solution was extracted with DCM, and the combinedorganic extracts were passed through a phase separation frit thenconcentrated in vacuo to afford the title compound (0.102 g, 0.439 mmol,84% yield) in sufficient purity for step 2. MS (apci) m/z=233.2 (M+H).

Step 2: Preparation ofN-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)acetamide

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.060 g, 0.213 mmol) in DMSO (1 mL) was added DIEA(0.184 mL, 1.06 mmol) and N-(4-benzylpiperidin-4-yl)acetamide (0.0988 g,0.425 mmol). The reaction mixture was stirred at 100° C. for 24 h. Aftercooling to ambient temperature, the reaction mixture was quenched withsaturated NH₄C_((aq)) and extracted into DCM. The combined organicextracts were dried over anhydrous Na₂SO_(4(s)) and concentrated invacuo. The residue was purified by silica chromatography (0-100% EtOAcin hexanes as the gradient eluent) to afford the title compound (0.072g, 0.146 mmol, 68.5% yield). MS (apci) m/z=495.2 (M+H).

Example 373

4-(6-(4-amino-4-benzylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution ofN-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)acetamide(Example 372, 0.020 g, 0.040 mmol) in 1:1 THF/DCM (0.7 mL) was addedtitanium(IV) propan-2-olate (0.048 mL, 0.16 mmol) and diphenylsilane(0.030 g, 0.16 mmol). The reaction mixture was stirred at rt for 24 hthen quenched with water. The mixture was extracted with DCM, and thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by preparative HPLC(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were combined and washed with 2M NaOH andextracted into DCM. The combined organic extracts were passed through aphase separation frit then concentrated in vacuo to afford the titlecompound (0.0030 g, 0.0066 mmol, 16% yield). MS (apci) m/z=453.3 (M+H).

Example 374

4-(6-(4-(benzylsulfonyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 21.3 m g, 0.0755 mmol) in DMA (0.35 mL) was added TEA(0.0526 mL, 0.377 mmol) and 4-(benzylsulfonyl)piperidine (52.4 mg, 0.219mmol). The reaction mixture was stirred at 90° C. for 16 h. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc and washed successively with water and saturated NaCl_((aq)). Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by C-18 reverse phasechromatography (5-95% ACN in water [+0.1% TFA] as the gradient eluent).The fractions containing the desired product were combined and washedwith saturated NaHCO_(3(aq)) and extracted into 4:1 DCM/IPA. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andconcentrated in vacuo. The residue was purified by silica chromatography(0-100% EtOAc in hexanes as the gradient eluent) to afford the titlecompound (13 mg, 0.0255 mmol, 34% yield). MS (apci) m/z=502.2 (M+H).

Example 375

tert-butyl((1R,5S,6r)-3-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 80 mg, 0.283 mmol) in DMSO (0.567 mL) was addedtert-butyl ((1R,5S,6r)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate (72.2mg, 0.340 mmol) and DIEA (0.148 mL, 0.850 mmol). The reaction mixturewas stirred at 90° C. for 17 h. After cooling to ambient temperature,the reaction mixture was diluted with water and stirred for 1 h. Theresultant precipitate was isolated by vacuum filtration and rinsed onthe filter successively with water and heptane to afford the titlecompound (130 mg, 0.266 mmol, 94% yield). MS (apci) m/z=475.2 (M+H).

Example 376

4-(6-((1R,5S,6r)-6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

To a solution of tert-butyl((1R,5S,6r)-3-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate(Example 375, 130 mg, 0.274 mmol) in MeOH (0.548 mL) was added HCl (37%w/w, 0.457 mL, 5.48 mmol) dropwise at rt. The reaction slurry wasstirred at rt for 3 h. The slurry was vacuum filtered, and the isolatedsolid was rinsed on the filter with MeOH and MTBE to afford the titlecompound (114 mg, 0.252 mmol, 92% yield). MS (apci) m/z=375.2 (M+H).

Example 377

6-ethoxy-4-(6-((1R,5S,6r)-6-((3-fluoro-6-methylpyridin-2-yl)amino)-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of4-(6-((1R,5S,6r)-6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 376, 25 mg, 0.056 mmol) and2,3-difluoro-6-methylpyridine (11 mg, 0.084 mmol) in DMSO (0.112 mL) wasadded DIEA (0.049 mL, 0.28 mmol). The reaction mixture was stirred at110° C. for 24 h then 150° C. for an additional 24 h. After cooling toambient temperature, the reaction mixture was directly purified by C-18reverse phase chromatography (5-95% ACN in water as the gradient eluent)to afford the title compound (7.7 mg, 0.015 mmol, 28%). MS (apci)m/z=484.2 (M+H).

Example 378

tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

To a solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(Intermediate P71, 0.225 g, 0.459 mmol), in DCE (2.29 mL) was added1-ethylpiperazine (0.157 g, 1.38 mmol). The mixture was stirred at rtfor 30 min, then sodium triacetoxyborohydride (0.146 g, 0.688 mmol) wasadded. The reaction mixture was stirred at rt an additional 16 h. Thecrude reaction mixture was directly purified by silica chromatography(1-10% MeOH in DCM with 0.1-1% NH₄OH as the gradient eluent) to affordthe title compound (0.149 mg, 0.253 mmol, 55% yield). MS (apci)m/z=589.4 (M+H).

Example 379

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P70, 0.0196 g, 0.03722 mmol) in DCE (0.1861 mL) was addedmorpholine (0.009661 mL, 0.1117 mmol) and sodium triacetoxyborohydride(0.01183 g, 0.05583 mmol). The reaction mixture was stirred at rt for 16h. The crude reaction mixture was directly purified by silicachromatography (0-100% EtOAc in Hexanes then 0-10% MeOH in CHCl₃ as thegradient eluent) to afford the title compound (0.0172 g, 0.02878 mmol,77% yield). MS (apci) m/z=598.3 (M+H).

The compounds in Table TT were prepared using a similar method to thatdescribed for the synthesis of Example 379, replacing morpholine withthe appropriate amine. Reactions were monitored for completion by LCMS,and reaction durations were adjusted accordingly. Title compounds werecleanly isolated following chromatographic purification using anappropriate gradient eluent (and if necessary converted to the freebase).

TABLE TT MS Ex. # Structure Chemical Name m/z 380

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(((3- hydroxypropyl)(methyl)ami- no)methyl)piperidin-4-yl)-5-fluoro-2- methylbenzamide 600.30 (M + H) 381

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(((2-hydroxy-2- methylpropyl)ami- no)methyl)piperidin-4-yl)-5-fluoro- 2-methylbenzamide 600.30 (M + H) 382

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(((2,2-difluoro-3- hydroxypropyl)(methyl)ami-no)methyl)piperidin-4-yl)- 5-fluoro-2- methylbenzamide 636.40 (M + H)

Example 383

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 7 mg, 0.017 mmol) in DMF (0.334 mL) was added5-fluoro-2-methylbenzoic acid (5.1 mg, 0.033 mmol), HATU (13 mg, 0.033mmol), and DIEA (0.015 mL, 0.083 mmol). The reaction mixture was stirredat rt for 1 h. The crude reaction mixture was directly purified bysilica chromatography (0-100% EtOAc in Hexanes then 1-10% MeOH in EtOAcwith 0.1-1% NH₄OH as the gradient eluent) to afford the title compound(5 mg, 0.0090 mmol, 54% yield). MS (apci) m/z=556.2 (M+H).

Example 384

3-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)picolinamide

To a mixture of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 0.050 g, 0.119 mmol) in DMSO (0.795 mL) was added3-chloropicolinic acid (0.0282 g, 0.179 mmol) followed by Hunig's base(0.0934 mL, 0.536 mmol) and HATU (0.0906 g, 0.238 mmol). The reactionmixture was stirred at rt for 16 h. The reaction mixture was dilutedwith EtOAc and washed with water. The organic extract was washed withsaturated NaCl_((aq)), dried over anhydrous Na₂SO_(4(s)), andconcentrated in vacuo. The residue was purified by preparative HPLC(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were combined and washed with saturatedNaHCO_(3(aq)) and extracted into DCM. The combined organic extracts werewashed with saturated NaCl_((aq)), dried over anhydrous Na₂SO_(4(s)),and concentrated in vacuo to afford the title compound (0.0108 g, 0.0193mmol, 16.2% yield). MS (apci) m/z=559.3 (M+H).

Example 385

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-methylbutanamide

To a solution of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 40 mg, 0.095 mmol) in DCM (0.953 mL) was added andisovaleryl chloride (11 mg, 0.095 mmol) and TEA (0.027 mL, 0.19 mmol).The reaction mixture was stirred at rt 3 h. The reaction mixture wasdiluted with 4:1 DCM:IPA and washed successively with saturatedNaHCO_(3(aq)), water, and saturated NaCl_((aq)). The organic extract wasdried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto afford the title compound (48 mg, 0.095 mmol, 100% yield). MS (apci)m/z=504.3 (M+H).

Example 386

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-2-cyclopropylacetamide

The compound was prepared using a similar method to that described forthe synthesis of Example 385, replacing isovaleryl chloride with the2-cyclopropylacetyl chloride. LCMS m/z=502.3 (M+H).

Example 387

1-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-isopropylurea

To a solution of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 30 mg, 0.072 mmol) and DIEA (125 μL, 0.715 mmol) inDMA (1.43 mL) was added 4-nitrophenyl chlorformate (17 mg, 0.086 mmol).The reaction mixture was stirred for 1 h at ambient temperature.Propan-2-amine (31 μL, 0.358 mmol) was added to the reaction mixture.The reaction mixture was stirred overnight at 80° C. The reactionmixture was cooled to ambient temperature and concentrated in vacuo. Theresidue was purified by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA. The combined organic extracts werewashed with brine, then dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to afford the title compound (4 mg, 11% yield). MS(apci) m/z=505.3 (M+H).

Example 388

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)-2-cyclopropylacetamide

To a solution of4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P73, 30 mg, 0.065 mmol) in DCM (0.650 mL) was added TEA(0.018 mL, 0.13 mmol) and cyclopropylacetyl chloride (9.2 mg, 0.078mmol). The reaction mixture was stirred at rt for 16 h. The reactionmixture was diluted with 4:1 DCM:IPA and washed successively withsaturated NaHCO_(3(aq)), water, and saturated NaCl_((aq)). The organicextract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (35 mg, 0.064 mmol,99% yield). MS (apci) m/z=544.3 (M+H).

Example 389

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution of4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P74. 20 mg, 0.0356 mmol) in DMF (0.356 mL)was added 5-fluoro-2-methylbenzoic acid (6.86 mg, 0.0445 mmol), DIEA(0.0311 mL, 0.178 mmol), and HATU (16.9 mg, 0.0445 mmol). The reactionmixture was stirred at rt for 5 min. The crude reaction mixture wasdirectly purified by silica chromatography (0-100% EtOAc in Hexanes then1-10% MeOH in EtOAc with 0.1-1% NH₄OH as the gradient eluent) to affordthe title compound (7 mg, 0.0112 mmol, 31.5% yield). MS (apci) m/z=625.4(M+H).

The compounds in Table UU were prepared using a similar method to thatdescribed for the synthesis of Example 389, replacing5-fluoro-2-methylbenzoic acid with the appropriate carboxylic acid.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE UU MS (apci) Ex. # Structure Chemical Name m/z 390

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1- yl)methyl)piperidin-4-yl)-3-(trifluoromethyl) picolinamide 662.20 (M + H)

Example 391

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide

To a solution of4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P74, 0.0238 g, 0.0606 mmol) in DMSO (0.606 mL) was addedDIEA (0.0530 ml, 0.303 mmol), 2,6-difluorobenzoic acid (0.0192 g, 0.121mmol), HATU (0.0461 g, 0.121 mmol). The reaction mixture was stirred atrt for 16 h. The crude reaction mixture was directly purified by silicachromatography (1-10% MeOH in DCM with 0.1-1% NH₄OH as the gradienteluent) to afford the title compound (29 mg, 0.023 mmol, 49.5% yield).MS (apci) m/z=629.4 (M+H).

Example 392

methyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

To a solution of4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P74, 0.0238 g, 0.0606 mmol) in DCM (0.48 mL) was addedDIEA (13 μL, 0.072 mmol) followed by methyl chloroformate (5 μL, 0.058mmol). The reaction mixture was stirred for 1 h at ambient temperature.The crude reaction mixture was filtered and the filtrate was directlypurified by silica chromatography (1-10% MeOH in DCM with 0.1-1% NH₄OHas the gradient eluent) to afford the title compound (1.9 mg, 7% yield).MS (apci) m/z=547.3 (M+H).

Example 393

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-2-cyclopropylacetamide

To a solution of4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P74, 50 mg, 0.10 mmol) in DMA (1.023 mL) was addedcyclopropylacetyl chloride (15 mg, 0.12 mmol) and TEA (0.029 mL, 0.20mmol). The reaction mixture was stirred at rt for 3 h. The reactionmixture was diluted with 4:1 DCM:IPA and washed successively withsaturated NaHCO_(3(aq)), water, and saturated NaCl_((aq)). The organicextract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (45 mg, 0.079 mmol,77% yield). MS (apci) m/z=571.4 (M+H).

Example 394

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide

The compound was prepared using a similar method to that described forthe synthesis of Example 393, replacing 2-cyclopropylacetyl chloridewith 3-methylbutanoyl chloride. MS (apci) m/z=573.4 (M+H).

Example 395

1-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-3-isopropylurea

To a solution of4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P74, 30 mg, 0.061 mmol) and DIEA (107 μL, 0.614 mmol) inDMA (1.228 mL) was added 4-nitrophenyl chlorformate (15 mg, 0.074 mmol).The reaction mixture was stirred for 1 h at ambient temperature beforepropan-2-amine (26.3 μl, 0.307 mmol). was introduced. The reactionmixture was stirred for 2 h at 80° C. The reaction mixture was cooled toambient temperature and concentrated in vacuo. The residue was purifiedby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated NaHCO_(3(aq)) and extracted with 4:1DCM:IPA. The combined organic extracts were washed with brine, thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (27 mg, 77% yield). MS (apci) m/z=574.4 (M+H).

Example 396

1-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-3-isobutylurea

The title compound was prepared using a similar method to that describedfor the synthesis of Example 395, replacing propan-2-amine with2-methylpropan-1-amine. MS (apci) m/z=588.4 (M+H).

Example 397

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-(morpholinomethyl)piperidine-4-carboxamide

To a solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 101.6 mg, 0.2141 mmol) in DCM (1.0 mL) was addedmorpholine (0.0942 mL, 1.070 mmol) and sodium triacetoxyborohydride(226.9 mg, 1.070 mmol). The reaction mixture was stirred at rt for 16 h.The reaction mixture was concentrated in vacuo, and the resultant cruderesidue was directly purified by C-18 reverse phase chromatography(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were diluted with 4:1 DCM:IPA and washedwith saturated NaHCO_(3(aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. The residuewas purified by silica chromatography (1-30% MeOH [+2% NH₄OH] in DCM asthe gradient eluent) afford the title compound (71.1 mg, 0.1303 mmol,60.86% yield). MS (apci) m/z=546.4 (M+H).

Example 398

4-(6-(4-benzyl-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P77, 10.4 mg, 0.0223 mmol) in DCE (0.75 mL) was addedmorpholine (9.1 mg, 0.104 mmol). The mixture was stirred at rt for 1 hrthen was treated with sodium triacetoxyborohydride (34.0 mg, 0.160mmol). The reaction mixture was stirred at rt for 96 h. The reactionmixture was diluted with DCM and washed with water. The organic extractwas dried over anhydrous Na₂SO_(4(s)) and purified by silicachromatography (0-100% EtOAc in hexanes as the gradient eluent to affordthe title compound (1.6 mg, 0.00295 mmol, 13.2% yield). MS (apci)m/z=537.3 (M+H).

Example 399

6-(2-(4-methylpiperazin-1-yl)ethoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of triphenylphosphane (31.7966 mg, 0.121 mmol) in 1:1 DCM:THF(0.6 mL) was cooled to 0° C. and treated with diisopropylazodicarboxylate (0.023 mL, 0.121 mmol) and stirred at 0° C. for 15 min.The reaction mixture was treated with6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P78, 25.0 mg, 0.0606 mmol) in a 1:1 DCM:THF (0.6 mL) and1-(N-hydroxyethyl)-4-methyl piperazine (13.1 mg, 0.0909 mmol). Thereaction mixture was allowed to warm to rt and was stirred at thistemperature for 30 min. The reaction mixture was concentrated in vacuo,and the resultant crude residue was directly purified by C-18 reversephase chromatography (5-95% ACN in water [+0.1% TFA] as the gradienteluent). The fractions containing the desired product were diluted with4:1 DCM:IPA and washed with saturated NaHCO_(3(aq)). The organic extractwas dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo to afford the title compound (31.5 mg, 0.0526 mmol, 86.8% yield).MS (apci) m/z=539.2 (M+H).

The compounds in Table VV were prepared using a similar method to thatdescribed for the synthesis of Example 399, replacing1-(N-hydroxyethyl)-4-methyl piperazine with the appropriate alcohol.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE VV MS Ex. # Structure Chemical Name m/z 400

6-(2- (dimethylamino)ethoxy)-4- (6-(4-(pyridin-2- yloxy)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 484.20 (M + H)401

6-(2-morpholinoethoxy)-4- (6-(4-(pyridin-2- yloxy)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 526.20 (M + H)402

6-(2-(1-methylazetidin-3- yl)ethoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin- 1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 510.20 (M + H) 403

6-((4-methylmorpholin-2- yl)methoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin- 1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 526.20 (M + H) 404

4-(6-(4-(pyridin-2- yloxy)piperidin-1- yl)pyridin-3-yl)-6-(2-(pyrrolidin-1- yl)ethoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 510.30(M + H)

Example 405

6-(2-(2-oxopyrrolidin-1-yl)ethoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P78, 0.010 g, 0.0242 mmol) in DMF (0.8 mL) was added1-(2-chloroethyl)pyrrolidin-2-one (7.16 mg, 0.0485 mmol), potassiumcarbonate (6.7 mg, 0.0485 mmol), and sodium bromide (3.24 mg, 0.0315mmol). The reaction mixture was stirred at 100° C. for 72 h. Aftercooling to ambient temperature, the crude reaction mixture purified byC-18 reverse phase chromatography (0-70% ACN in water as the gradienteluent) to afford the title compound (8 mg, 0.0153 mmol, 63% yield). MS(apci) m/z=524.2 (M+H).

The compounds in Table WW were prepared using a similar method to thatdescribed for the synthesis of Example 405, replacing1-(2-chloroethyl)pyrrolidin-2-one with the appropriate alkyl halide.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE WW MS Ex. # Structure Chemical Name m/z 406

2-((3-cyano-4-(6-(4- (pyridin-2-yloxy)piperidin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)acetamide 470.10 (M + H) 407

2-((3-cyano-4-(6-(4- (pyridin-2-yloxy)piperidin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)-N- methylacetamide 484.10 (M + H)408

2-((3-cyano-4-(6-(4- (pyridin-2-yloxy)piperidin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)-N,N- dimethylacetamide 498.15 (M +H)

Example 409

(R)-6-(2-hydroxypropoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P78, 1.023 mL, 0.0512 mmol) in DMF (1.0 mL) was addedaqueous sodium hydroxide (1M, 0.0563 mL, 0.0563 mmol). The mixture wasstirred at rt for 5 min, at which time R-(+)-propylene oxide (35.8 μL,0.512 mmol) was added. The reaction mixture was stirred at 80° C. for 16h. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc then washed successively with water and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The residue was purified by C-18reverse phase chromatography (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werediluted with 4:1 DCM/IPA and washed with saturated NaHCO_(3(aq)). Theorganic extract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (8.5 mg, 0.0181 mmol,35.3% yield). MS (apci) m/z=471.2 (M+H).

Example 410

(S)-6-(2-hydroxypropoxy)-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared using a similar method to that describedfor the synthesis of Example 409, replacing R-(+)-propylene oxide withS-(−)-propylene oxide. MS (apci) m/z=471.2 (M+H).

Example 411

4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P79, 19.7 mg, 0.05362 mmol) in DMSO (1 mL) was added4-(pyridin-2-ylmethyl)piperidin-4-ol hydrochloride (39.3 mg, 0.1718mmol) and cesium carbonate (157.2 mg, 0.4826 mmol). The reaction mixturewas stirred at 60° C. for 16 h. After cooling to ambient temperature,the reaction mixture was diluted with DCM and washed successively withwater and saturated NH₄Cl_((aq)). The aqueous fraction was extractedwith DCM, and the combined organic extracts were dried over anhydrousNa₂SO_(4(s)). The mixture was purified by silica chromatography (0-100%MeOH in DCM as the gradient eluent) to afford the title compound (16.9mg, 0.02505 mmol, 46.72% yield). MS (apci) m/z=540.2 (M+H).

The compounds in Table XX were prepared using a similar method to thatdescribed for the synthesis of Example 411, replacing4-(pyridin-2-ylmethyl)piperidin-4-ol hydrochloride with the appropriateamine. Reactions were monitored for completion by LCMS, and reactiondurations were adjusted accordingly. Title compounds were cleanlyisolated following chromatographic purification using an appropriategradient eluent (and if necessary converted to the free base).

TABLE XX MS Ex. # Structure Chemical Name m/z 412

4-(6-(4-benzyl-4- hydroxypiperidin-1- yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo [1,5-a]pyridine-3- carbonitrile 539.20 (M + H)413

6-(2-morpholinoethoxy)-4- (6-(3-(pyridin-2- yloxy)azetidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 498.20 (M + H)

Example 414

6-(2-methoxyethoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of6-hydroxy-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P66, 0.250 g, 0.9834 mmol) in DMA (2.458 mL) was added2-(azetidin-3-yloxy)pyridine (0.452 g, 3.010 mmol) and TEA (0.9413 mL,6.884 mmol). The reaction mixture was stirred at 95° C. for 72 h. Aftercooling to ambient temperature, the reaction mixture was quenched withsaturated NaHCO_(3(aq)) and extracted with EtOAc. The combined organicextracts were washed successively with water and saturated NaCl_((aq))then dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The residue was purified by silica chromatography (1-9% MeOH inDCM as the gradient eluent) to afford the title compound (0.1557 g,0.4050 mmol, 41.19% yield) in sufficient purity for step 2. MS (apci)m/z=385.1 (M+H).

Step 2: Preparation of6-(2-methoxyethoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-hydroxy-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.030 g, 0.07804 mmol) in DMF (0.3902 mL) was added potassium carbonate(0.02157 g, 0.1561 mmol) and 2-bromoethyl methyl ether (0.01467 mL,0.1561 mmol). The reaction mixture was stirred at 95° C. for 16 h. Aftercooling to ambient temperature, the reaction mixture was quenched withsaturated NaHCO_(3(aq)) and extracted with EtOAc. The combined organicextracts were washed successively with water and saturated NaCl_((aq))then dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The residue was purified by preparative HPLC (5-95% ACN in water[+0.1% TFA] as the gradient eluent). The fractions containing thedesired product were washed with saturated NaHCO_(3(aq)) and extractedwith DCM. The combined organic extracts were washed successively withwater and saturated NaCl_((aq)) then dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (0.0108g, 0.02441 mmol, 31.27% yield). MS (apci) m/z=443.2 (M+H).

Example 415

(R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of(R)-4-(6-fluoropyridin-3-yl)-6-(2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P80, 0.020 g, 0.0640 mmol) in DMA (0.640 mL) was added3-methyl-6-(piperidin-4-yloxy)pyridazine (0.039 g, 0.202 mmol) and TEA(0.0613 ml, 0.448 mmol). The reaction mixture was stirred at 90° C. for48 h. After cooling to ambient temperature, the reaction mixture wasquenched with water and extracted with EtOAc. The combined organicextracts were washed successively with water and saturated NaCl_((aq))then dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo. The residue was purified by preparative HPLC (5-95% ACN in water[+0.1% TFA] as the gradient eluent). The fractions containing thedesired product were washed with saturated NaHCO_(3(aq)) and extractedwith DCM. The combined organic extracts were washed successively withwater and saturated NaCl_((aq)) then dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (11 mg,0.022 mmol, 34% yield). MS (apci) m/z=486.2 (M+H).

Example 416

(R)-6-(2-hydroxypropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The compound was prepared using a similar method to that described forthe synthesis of Example 415, replacing3-methyl-6-(piperidin-4-yloxy)pyridazine with2-(azetidin-3-yloxy)pyridine. MS (apci) m/z=443.1 (M+H).

Example 417

3-chloro-6-methoxy-4-(6-(4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridineStep 1: Preparation of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine

To a mixture of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (10.0 g, 44.04mmol) in 1,4-dioxane (88.08 mL) was added2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (11.79g, 52.85 mmol), tetrakis(triphenylphosphine)palladium(0) (1.018 g,0.8808 mmol) and aqueous sodium carbonate (2M, 46.24 mL, 92.49 mmol).The reaction mixture was stirred at 90° C. for 16 h. After cooling toambient temperature, the reaction mixture was poured onto water andstirred for 4 h. The resultant precipitate was isolated by vacuumfiltration then taken up in MTBE and stirred an additional 30 min. Theprecipitate was isolated by vacuum filtration to afford the titlecompound (4.616 g, 18.98 mmol, 43.09% yield) in sufficient yield forstep 2. MS (apci) m/z=244.0 (M+H).

Step 2: Preparation of3-chloro-4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine

A solution of 4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine(1.00 g, 4.11 mmol) in DCM (27.4 mL) was treated with NCS (0.549 g, 4.11mmol). The reaction mixture was stirred at rt for 16 h. The mixture waspoured into 2M NaOH and extracted with 10% IPA in DCM in a PS frit. Theorganic extract was concentrated in vacuo, and the residue wastriturated with Et₂O. The solid was isolated on a glass frit to affordthe title compound (0.98 g, 3.53 mmol, 85.8% yield) in sufficient purityfor step 3. MS (apci) m/z=278.0 (M+H).

Step 3: Preparation of3-chloro-6-methoxy-4-(6-(4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

To a solution of3-chloro-4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine (30mg, 0.11 mmol) in DMSO (0.2 mL) was added3-methyl-6-(piperidin-4-yloxy)pyridazine (31 mg, 0.16 mmol) and cesiumcarbonate (176 mg, 0.54 mmol). The reaction mixture was stirred at 90°C. for 16 h. After cooling to ambient temperature, the mixture waspoured into 2M NaOH and extracted with 10% IPA in DCM in a PS frit. Theorganic extract was concentrated in vacuo, and the residue was purifiedby silica chromatography (0-100% EtOAc in hexanes as the gradienteluent) to afford the title compound (14 mg, 0.031 mmol, 29% yield). MS(apci) m/z=451.2 (M+H).

Example 418

3-chloro-N-(1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a mixture of1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine(0.057 g, 0.169 mmol) in DMSO (1.13 mL) was added 3-chloropicolinic acid(0.0399 g, 0.253 mmol), DIEA (0.132 mL, 0.760 mmol), and HATU (0.128 g,0.338 mmol). The reaction mixture was stirred at rt for 16 h. Thereaction mixture was diluted with EtOAc and washed successively withwater and saturated NaCl_((aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), and concentrated in vacuo. The residue waspurified by preparative HPLC (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werediluted with DCM and washed successively with saturated NaHCO_(3(aq))and saturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (0.0501 g, 0.105 mmol, 62.2% yield). MS (apci) m/z=477.2 (M+H).

The compounds in Table YY were prepared using a similar method to thatdescribed for the synthesis of Example 418, replacing 3-chloropicolinicacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent (and if necessaryconverted to the free base).

TABLE YY MS (apci) Ex. # Structure Chemical Name m/z 419

2-chloro-6-fluoro-N-(1-(5- (6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)benzamide 494.20(M + H) 420

2-chloro-5-fluoro-N-(1-(5- (6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)benzamide 494.20(M + H)

Example 421

3-chloro-N-(1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a mixture of1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine(0.057 g, 0.153 mmol) in DMSO (1.02 mL) was added 3-chloropicolinic acid(0.0362 g, 0.230 mmol), DIEA (0.120 mL, 0.690 mmol), and HATU (0.117 g,0.307 mmol). The reaction mixture was stirred at rt for 16 h. Thereaction mixture was diluted with EtOAc and washed successively withwater and saturated NaCl_((aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), and concentrated in vacuo. The residue waspurified by silica chromatography (10-99% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.0415 g, 0.0811 mmol,52.9% yield). MS (apci) m/z=511.2 (M⁺).

The compounds in Table ZZ were prepared using a similar method to thatdescribed for the synthesis of Example 421, replacing 3-chloropicolinicacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.Title compounds were cleanly isolated following chromatographicpurification using an appropriate gradient eluent (and if necessaryconverted to the free base).

TABLE ZZ MS Ex. # Structure Chemical Name m/z 422

2-chloro-N-(1-(5-(3- chloro-6- methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)-6-fluorobenzamide528.20 (M⁺) 423

2-chloro-N-(1-(5-(3- chloro-6- methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)-5-fluorobenzamide528.20 (M⁺)

Example 424

3-chloro-N-(1-(5-(3-cyclopropyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamideStep 1: Preparation of tert-butyl(1-(5-(3-bromo-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of tert-butyl(1-(5-(6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate P81, 0.806 g, 1.84 mmol) in DCM (12.3 mL) was added NBS(0.328 g, 1.84 mmol). The reaction mixture was stirred at rt for 16 h.The reaction mixture was diluted with EtOAc and washed successively withwater and saturated NaCl_((aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), and concentrated in vacuo. The residue waspurified by silica chromatography (10-90% EtOAc in hexanes as thegradient eluent) to afford the title compound (0.839 g, 1.62 mmol, 88%yield) in sufficient purity for step 2. MS (apci) m/z=518.1 (M+H+1).

Step 2: Preparation of tert-butyl(1-(5-(3-cyclopropyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate.To a mixture of tert-butyl(1-(5-(3-bromo-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(0.250 g, 0.484 mmol) in a biphasic mixture of toluene (2.42 mL) andwater (0.4 mL) was added cyclopropylboronic acid (0.0832 g, 0.968 mmol),potassium phosphate (0.308 g, 1.45 mmol), palladium(II) acetate (0.0109g, 0.0484 mmol) and tricyclopentylphosphine (0.0272 g, 0.0968 mmol). Thereaction mixture was stirred at 90° C. for 16 h. After cooling toambient temperature, the reaction mixture was diluted with EtOAc andwashed successively with water and saturated NaCl_((aq)). The organicextract was dried over anhydrous Na₂SO_(4(s)), and concentrated invacuo. The residue was purified by silica chromatography (10-90% EtOAcin hexanes as the gradient eluent) to afford the title compound (0.061g, 0.128 mmol, 26% yield) in sufficient purity for step 3. MS (apci)m/z=478.3 (M+H).

Step 3: Preparation of1-(5-(3-cyclopropyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine

A solution of tert-butyl(1-(5-(3-cyclopropyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(0.060 g, 0.13 mmol) in DCM (12 mL) was treated with TFA (12 mL). Thereaction mixture was stirred at rt for 1 h. The reaction mixture wasdiluted with DCM and washed with saturated NaHCO_(3(aq)). The organicextract was dried over anhydrous Na₂SO_(4(s)), and concentrated in vacuoto afford the title compound (0.047 g, 0.12 mmol, 99% yield) insufficient purity for step 4. MS (apci) m/z=378.2 (M+H).

Step 4: Preparation of3-chloro-N-(1-(5-(3-cyclopropyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide.To a mixture of1-(5-(3-cyclopropyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine(0.047 g, 0.125 mmol) in DMSO (0.830 mL) was added 3-chloropicolinicacid (0.0294 g, 0.187 mmol), DIEA (0.0976 mL, 0.560 mmol), and HATU(0.0947 g, 0.249 mmol). The reaction mixture was stirred at rt for 16 h.The reaction mixture was diluted with EtOAc and washed successively withwater and saturated NaCl_((aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), and concentrated in vacuo. The residue waspurified by preparative HPLC (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werediluted with DCM and washed successively with saturated NaHCO_(3(aq))and saturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (0.0441 g, 0.0853 mmol, 68.5% yield). MS (apci) m/z=517.2 (M⁺).

Example 425

(3S,4S)-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((6-methoxypyridin-3-yl)oxy)pyrrolidin-3-amineStep 1: Preparation of 4-bromo-3-chloro-6-ethoxypyrazolo[1,5-a]pyridine

To a solution of 4-bromo-3-chloropyrazolo[1,5-a]pyridin-6-ol(Intermediate P84, 2.5 g, 10.1 mmol) in DMA (150 mL) was added potassiumcarbonate (14.0 g, 101 mmol) and iodoethane (2.45 mL, 30.3 mmol). Thereaction mixture was stirred at 65° C. for 16 h. After cooling toambient temperature, the reaction mixture was quenched with water andextracted with EtOAc. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), and concentrated in vacuo to afford the titlecompound (2.00 g, 7.26 mmol, 72% yield) in sufficient purity for step 2.MS (apci) m/z=277.0 (M+H).

Step 2: Preparation of3-chloro-6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine

To a solution of 4-bromo-3-chloro-6-ethoxypyrazolo[1,5-a]pyridine (1.0g, 3.6 mmol) in 1,4-dioxane (18 mL) was added2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.1 g,4.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.18mmol), and aqueous sodium carbonate (2M, 9.1 mL, 18 mmol). The reactionmixture was sparged with N₂ and stirred at 90° C. for 4 h. After coolingto ambient temperature, the reaction mixture was quenched with water andsonicated for 5 min. The resultant precipitate was isolated by vacuumfiltration and washed on the filter with Et₂O to afford the titlecompound (0.4 g, 1.4 mmol, 38% yield) in sufficient purity for step 3.MS (apci) m/z=292.1 (M+H).

Step 3: Preparation of tert-butyl((3S,4R)-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate.To a solution of3-chloro-6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine (0.100g, 0.343 mmol) in DMSO (1 mL) was added DIEA (0.296 mL, 1.71 mmol) andtert-butyl ((3S,4R)-4-hydroxypyrrolidin-3-yl)carbamate (0.139 g, 0.686mmol). The reaction mixture was stirred at 95° C. for 16 h. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and cooled to 0° C. The resultant precipitate was isolated byvacuum filtration then taken up in 1:1 MTBE/pentane. The slurry wassonicated for 20 min, and the solids were isolated by vacuum filtrationto afford the title compound (0.148 g, 0.312 mmol, 91.1% yield) insufficient purity for step 4. MS (apci) m/z=474.15 (M+H).

Step 4: Preparation of(3S,4S)-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((6-methoxypyridin-3-yl)oxy)pyrrolidin-3-amine.To a solution of tert-butyl((3S,4R)-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(0.040 g, 0.0844 mmol) in 1:1 THF/DCM (0.8 mL) was added6-methoxypyridin-3-ol (0.0211 g, 0.169 mmol) and triphenylphosphane(0.0443 g, 0.169 mmol). The reaction mixture was sparged with argon andstirred at rt for 16 h. The reaction mixture was quenched with saturatedNH₄Cl_((aq)) and extracted with DCM. The combined organic extracts weredried using a PS frit, concentrated in vacuo, and purified by silicachromatography (0-100% EtOAc in hexanes as the gradient eluent). Thefractions containing the desired product were concentrated in vacuo, andthe residue was taken up in 6M HCl in IPA and stirred for 2 h. Themixture was concentrated in vacuo, taken up in water and 2M NaOH, thenextracted with DCM. The combined organic extracts were dried using a PSfrit, concentrated in vacuo, and purified by silica chromatography(0-35% [9:1 MeOH/NH₄OH] in EtOAc as the gradient eluent to afford thetitle compound (0.004 g, 0.00832 mmol, 9.85% yield). MS (apci) m/z=481.2(M+H).

Example 426

4-((1-(5-(3-chloro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile

To a solution of1-((3-chloro-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-ol(Intermediate P85, 0.026 g, 0.077 mmol) in DMA (0.5 mL) was added TEA(0.024 g, 0.23 mmol) and 4-(piperidin-4-yloxy)benzonitrile (0.023 g,0.12 mmol). The reaction mixture was stirred at 105° C. for 16 h. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and extracted with DCM. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), concentrated in vacuo, and purified bysilica chromatography (0-100% EtOAc in hexanes as the gradient eluent)to afford the title compound (0.012 g, 0.023 mmol, 30% yield). MS (apci)m/z=518.2 (M+H).

The compounds in Table AAA were prepared using a similar method to thatdescribed for the synthesis of Example 426, replacing4-(piperidin-4-yloxy)benzonitrile with the appropriate amine reagent.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base). Table AAA

TABLE AAA MS Ex. # Structure Chemical Name m/z 427

1-((3-chloro-4-(6-(4- (pyridin-2-yloxy)piperidin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)-2-methylpropan- 2-ol 494.20 (M + H)428

(S)-1-((3-chloro-4-(6-(3- (pyridin-2- yloxy)pyrrolidin-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)-2-methylpropan- 2-ol 480.20 (M + H)429

(R)-1-((3-chloro-4-(6-(3- (pyridin-2- yloxy)pyrrolidin-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)-2-methylpropan- 2-ol 480.20 (M + H)430

1-((3-chloro-4-(6-(4- (phenylamino)piperidin-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)-2-methylpropan- 2-ol 492.20 (M + H)431

1-((3-chloro-4-(6-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridin- 6-yl)oxy)-2-methylpropan- 2-ol524.20 (M + H)

Example 432

3-chloro-N-(1-(5-(3-cyano-6-(3-(pyrrolidin-1-yl)propoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide

To a solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide(Intermediate P86, 0.035 g, 0.0692 mmol) in DMA (0.692 mL) was addedpotassium carbonate (0.0478 g, 0.346 mmol). The reaction mixture wassparged with argon, then 1-(3-chloropropyl)-pyrrolidine (0.0204 g, 0.138mmol) was added, and the reaction mixture was stirred at 60° C. for 5 h.After cooling to ambient temperature, the reaction mixture was directlypurified by preparative HPLC (5-75% ACN in water [+2% TFA] as thegradient eluent). The fractions containing the desired product werediluted with 4:1 DCM/IPA and washed successively with saturatedNaHCO_(3(aq)) and saturated NaCl_((aq)). The organic extract was driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo toafford the title compound (0.0186 g, 0.0301 mmol, 43.6% yield). MS(apci) m/z=617.3 (M+H).

The compounds in Table BBB were prepared using a similar method to thatdescribed for the synthesis of Example 432, replacing1-(3-chloropropyl)-pyrrolidine with the appropriate alkyl halide.Reactions were monitored for completion by LCMS, and reaction durationswere adjusted accordingly. Title compounds were cleanly isolatedfollowing chromatographic purification using an appropriate gradienteluent (and if necessary converted to the free base).

TABLE BBB MS Ex. # Structure Chemical Name m/z 433

3-chloro-N-(1-(5-(3- cyano-6-(3- morpholinopropoxy)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-4- methylpiperidin-4-yl)-5-fluoropicolinamide 633.30 (M + H) 434

3-chloro-N-(1-(5-(3- cyano-6- methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide 520.2 (M + H) 435

3-chloro-N-(1-(5-(3- cyano-6-(2- methoxyethoxy)pyrazolo1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide 564.20 (M + H) 436

3-chloro-N-(1-(5-(3- cyano-6-(2- (dimethylamino)ethoxy)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-4- methylpiperidin-4-yl)-5-fluoropicolinamide 577.20 (M + H)

Example 437

N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(Intermediate P87, 30.3 mg, 0.0670 mmol) in DMA (0.7 mL) was added4-(2-chloroethyl)morpholine hydrochloride (24.9 mg, 0.134 mmol) andcesium carbonate (109 mg, 0.335 mmol). The reaction mixture was stirredat 60° C. for 16 h. After cooling to ambient temperature, the reactionmixture was diluted with EtOAc and washed successively with water andsaturated NaCl_((aq)), dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The residue was purified by C-18 reverse phasechromatography (5-95% ACN in water [+0.1% TFA] as the gradient eluent).The fractions containing the desired product were diluted with 4:1DCM/IPA and washed with saturated NaHCO_(3(aq)). The organic extract wasdried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto afford the title compound (22.3 mg, 0.0394 mmol, 58.9% yield). MS(apci) m/z=566.3 (M+H).

The compounds in Table CCC were prepared using a similar method to thatdescribed for the synthesis of Example 437, replacing4-(2-chloroethyl)morpholine hydrochloride with the appropriate alkylhalide. Reactions were monitored for completion by LCMS, and reactiondurations were adjusted accordingly. Title compounds were cleanlyisolated following chromatographic purification using an appropriategradient eluent (and if necessary converted to the free base).

TABLE CCC MS Ex. # Structure Chemical Name m/z 438

N-(1-(5-(3-cyano-6-((1- methyl-1H-imidazol-4- yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)benzamide 547.30(M + H) 439

N-(1-(5-(3-cyano-6-(2- (pyrrolidin-1- yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)benzamide 550.30(M + H) 440

N-(1-(5-(3-cyano-6-(3- morpholinopropoxy) pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)benzamide 580.30 (M + H)

Example 441

N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

Step 1: Preparation of tert-butyl3-(((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate.To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(Intermediate P87, 44.8 mg, 0.0990 mmol) in DMA (1 mL) was addedtert-butyl 3-(bromomethyl)-3-fluoroazetidine-1-carboxylate (53.1 mg,0.198 mmol) and cesium carbonate (161 mg, 0.495 mmol). The reactionmixture was stirred at 60° C. for 16 h. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc and washedsuccessively with water and brine. The organic extract was dried overanhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo to affordthe title compound (assumed theoretical yield, 63 mg, 0.099 mmol) insufficient purity for step 2. MS (apci) m/z=640.25 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide.A solution of tert-butyl3-(((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylatein DCM (0.5 mL) was treated with TFA (0.5 mL, 6.5 mmol). The reactionmixture was stirred at rt for 30 min then concentrated in vacuo. Theresultant crude residue was directly purified by C-18 reverse phasechromatography (5-95% ACN in water [+0.1% TFA] as the gradient eluent).The fractions containing the desired product were diluted with 4:1DCM/IPA and washed with saturated NaHCO_(3(aq)). The organic extract wasdried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto afford the title compound (29.5 mg, 0.055 mmol, 55.2% yield over twosteps). MS (apci) m/z=540.3 (M+H).

Step 3: Preparation ofN-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide.To a solution ofN-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(29.5 mg, 0.055 mmol) in 1:1 DCM:MeOH (1.1 mL) was added formaldehyde(21 μL, 0.273 mmol) was added, followed by NaBH(AcO)₃ (58 mg, 0.273mmol) The resulting reaction mixture was allowed to stir 30 min atambient temperature. The reaction was concentrated in vacuo. The residuewas purified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (24 mg, 78% yield). MS (apci) m/z=554.3 (M+H).

Example 442

N-(1-(5-(3-cyano-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

To a solution ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(Intermediate P88, 32.7 mg, 0.0579 mmol) in 1:1 DCM/MeOH (1 mL) wasadded formaldehyde (0.0218 mL, 0.290 mmol) and sodiumtriacetoxyborohydride (61.4 mg, 0.290 mmol). The reaction mixture wasstirred at rt for 16 h then concentrated in vacuo. The residue wasdirectly purified by C-18 reverse phase chromatography (5-95% ACN inwater [+0.1% TFA] as the gradient eluent). The fractions containing thedesired product were diluted with 4:1 DCM/IPA and washed with saturatedNaHCO_(3(aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (21.4 mg, 0.0370 mmol, 63.9% yield). MS (apci) m/z=579.4 (M+H).

Example 443

N-(1-(5-(3-cyano-6-(2-(4-ethylpiperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

The compound was prepared using a similar method to that described forthe synthesis of Example 442, replacing formaldehyde with acetaldehyde.MS (apci) m/z=593.4 (M+H).

Example 444

N-(1-(5-(6-(2-(4-acetylpiperazin-1-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

To a solution ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(Intermediate P88, 46.4 mg, 0.0822 mmol) in DCM (1 mL) was added TEA(0.0557 mL, 0.411 mmol) then acetyl chloride (0.164 mL, 0.164 mmol). Thereaction mixture was stirred at rt for 16 h then concentrated in vacuo.The residue was directly purified by C-18 reverse phase chromatography(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were diluted with 4:1 DCM/IPA and washedwith saturated NaHCO_(3(aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. The residuewas purified by silica chromatography (1-30% [MeOH+2% NH₄OH] in DCM asthe gradient eluent) to afford the title compound (24.7 mg, 0.0407 mmol,49.5% yield). MS (apci) m/z=607.4 (M+H).

Example 445

N-(1-(5-(3-cyano-6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

Step 1: Preparation of tert-butyl(2-((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate.To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(Intermediate P87, 64.2 mg, 0.142 mmol) in DMA (1.5 mL) was added2-(Boc-amino)ethyl bromide (63.6 mg, 0.284 mmol) and cesium carbonate(231 mg, 0.709 mmol). The reaction mixture was stirred at 60° C. for 16h. After cooling to ambient temperature, the reaction mixture wasdiluted with EtOAc and washed successively with water and saturatedNaCl_((aq)), dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (assumed theoreticalyield, 84.6 mg, 0.142 mmol) in sufficient purity for step 2. MS (apci)m/z=596.3 (M+H).

Step 2: Preparation ofN-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide

A solution of tert-butyl(2-((4-(6-(4-benzamido-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate(84.6 mg, 0.142 mmol) in DCM (0.75 mL) was treated with TFA (0.75 mL,9.8 mmol). The reaction mixture was stirred at rt for 30 min thenconcentrated in vacuo. The residue was directly purified by C-18 reversephase chromatography (5-95% ACN in water [+0.1% TFA] as the gradienteluent). The fractions containing the desired product were diluted with4:1 DCM/IPA and washed with saturated NaHCO_(3(aq)). The organic extractwas dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo to afford the title compound (17.9 mg, 0.0361 mmol, 25.5% yieldover two steps). MS (apci) m/z=496.2 (M+H).

Step 3: Preparation ofN-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide.To a solution ofN-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide(18 mg, 0.036 mmol) in 1:1 DCM:MeOH (0.5 mL) was added formaldehyde (27μL, 0.36 mmol) was added, followed by NaBH(AcO)₃ (77 mg, 0.36 mmol) Theresulting reaction mixture was allowed to stir 16 h at ambienttemperature. The reaction was concentrated in vacuo. The residue waspurified directly by C18 reverse phase chromatography (5-95% ACN inwater with 0.1% TFA as the gradient eluent) to afford the title compoundas the TFA salt. The TFA salt was treated with saturated NaHCO_(3(aq))and extracted with 4:1 DCM:IPA. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (9 mg, 49% yield). MS (apci) m/z=524.3 (M+H).

Example 446

tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 106.2 mg, 0.3762 mmol) in DMSO (1 mL) was addedtert-butyl (4-methylpiperidin-4-yl)carbamate (201.6 mg, 0.9406 mmol) andcesium carbonate (858.1 mg, 2.634 mmol). The reaction mixture wasstirred at 60° C. for 16 h. After cooling to ambient temperature, thereaction mixture was diluted with water and extracted into DCM. Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)) andpurified by silica chromatography (0-100% EtOAc in hexanes as thegradient eluent) to afford the title compound (159.2 mg, 0.3274 mmol,87.01% yield). MS (apci) m/z=477.2 (M+H).

Example 447

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P89, 25.6 mg, 0.0680 mmol) in DCM (0.136 mL) was added2-picolinic acid (10.9 mg, 0.0884 mmol), HATU (31.0 mg, 0.0816 mmol),and DIEA (0.0474 mL, 0.272 mmol). The reaction mixture was stirred at rtfor 72 h. After cooling to ambient temperature, the reaction mixture waswashed with water and concentrated in vacuo. The residue was purified bysilica chromatography (50-100% EtOAc in hexanes then 0-10% MeOH in EtOAcas the gradient eluent) to afford the title compound (23 mg, 0.0473mmol, 70% yield). MS (apci) m/z=482.2 (M+H).

Example 448

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)nicotinamide

The title compound was prepared using a similar method to that describedfor the synthesis of Example 447, replacing 2-picolinic acid withnicotinic acid. MS (apci) m/z=482.2 (M+H).

Example 449

6-ethoxy-4-(6-(4-((5-fluoro-2-methylbenzyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride (Intermediate P89, 26 mg, 0.0630 mmol) in DMF (0.315 mL)was added TEA (0.018 mL, 0.126 mmol) and stirred for 5 min, at whichtime 5-fluoro-2-methylbenzaldehyde (13.0 mg, 0.0944 mmol) and sodiumtriacetoxyborohydride (66.7 mg, 0.315 mmol) was added. The reactionmixture was stirred at rt then purified by silica chromatography (0-100%EtOAc in hexanes as the gradient eluent) to afford the title compound(20 mg, 0.0401 mmol, 63.7% yield). MS (apci) m/z=499.2 (M+H).

Example 450

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-cyclopropylacetamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P89, 4.3 mg, 0.0114 mmol) in DCM (0.5 mL) was added DIEA(2.95 mg, 0.0228 mmol) and 2-cyclopropylacetyl chloride (1.63 mg, 0.0137mmol). The reaction mixture was stirred at rt for 2 h then diluted with4:1 DCM/IPA. The mixture was washed successively with 2M HCl, water, andsaturated NaHCO_(3(aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, concentrated in vacuo, and purified by silicachromatography (0-100% EtOAc in hexanes as the gradient eluent) toafford the title compound (2.3 mg, 0.00502 mmol, 43.9% yield). MS (apci)m/z=459.2 (M+H).

The compounds in Table DDD were prepared using a similar method to thatdescribed for the synthesis of Example 450, replacing2-cyclopropylacetyl chloride with the appropriate acyl chloride orchloroformate. Reactions were monitored for completion by LCMS, andreaction durations were adjusted accordingly. Title compounds werecleanly isolated following chromatographic purification using anappropriate gradient eluent (and if necessary converted to the freebase).

TABLE DDD MS Ex. # Structure Chemical Name m/z 451

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4- yl)-3-methylbutanamide 461.20 (M + H) 452

isopropyl (1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)carbamate 463.20(M + H)

Example 453

N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P90, 40 mg, 0.0882 mmol) in DMA (0.882 mL) was added4-(2-chloroethyl)morpholine hydrochloride (32.8 mg, 0.176 mmol) andcesium carbonate (144 mg, 0.441 mmol). The reaction mixture was stirredat 60° C. for 16 h. After cooling to ambient temperature, the reactionmixture was diluted with 4:1 DCM/IPA and washed successively with waterand saturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, concentrated in vacuo, and purified by C-18reverse phase chromatography (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werediluted with 4:1 DCM/IPA and washed with saturated NaHCO_(3(aq)) andsaturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (15.0 mg, 0.0265 mmol, 30.0% yield). MS (apci) m/z=567.3 (M+H).

The compounds in Table EEE were prepared using a similar method to thatdescribed for the synthesis of Example 453, replacing4-(2-chloroethyl)morpholine hydrochloride with the appropriate alkylhalide. Reactions were monitored for completion by LCMS, and reactiondurations were adjusted accordingly. Title compounds were cleanlyisolated following chromatographic purification using an appropriategradient eluent (and if necessary converted to the free base).

TABLE EEE MS Ex. # Structure Chemical Name m/z 454

N-(1-(5-(3-cyano-6-((1- methyl-1H-imidazol-4- yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)picolinamide548.30 (M + H) 455

N-(1-(5-(3-cyano-6-(3- morpholinopropoxy) pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)picolinamide 581.30 (M + H)456

N-(1-(5-(6-(2-(1H- imidazol-1-yl)ethoxy)-3- cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)picolinamide548.30 (M + H) 457

N-(1-(5-(3-cyano-6-((1- methyl-1H-imidazol-2- yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)picolinamide548.30 (M + H) 458

N-(1-(5-(3-cyano-6-(2- (pyrrolidin-1- yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)picolinamide551.30 (M + H)

Example 459

N-(1-(5-(6-(azetidin-3-ylmethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl3-(((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)azetidine-1-carboxylate.To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P90, 40 mg, 0.088 mmol) in DMA (0.882 mL) was added3-bromomethyl-azetidine-1-carboxylic acid tert-butyl ester (22 mg, 0.088mmol) and cesium carbonate (144 mg, 0.44 mmol). The reaction mixture wasstirred at 60° C. for 16 h. After cooling to ambient temperature thereaction mixture was diluted with 4:1 DCM/IPA and washed successivelywith water and saturated NaCl_((aq)). The organic extract was dried overanhydrous Na₂SO_(4(s)), filtered, concentrated in vacuo, and purified byC-18 reverse phase chromatography (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werediluted with 4:1 DCM/IPA and washed with saturated NaHCO_(3(aq)) andsaturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (15.0 mg, 0.0265 mmol, 30.0% yield) in sufficient purity forstep 2. MS (apci) m/z=623.3 (M+H).

Step 2: Preparation ofN-(1-(5-(6-(azetidin-3-ylmethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide.A solution of tert-butyl3-(((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)azetidine-1-carboxylate(55 mg, 0.088 mmol) in 1:1 (v/v) mixture of DCM:TFA (883 μL) was stirredat rt for 16 h. The reaction mixture was diluted with 4:1 DCM/IPA andwashed successively with saturated NaHCO_(3(aq)) and brine. The organicextract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (46 mg, 0.088 mmol,100% yield). MS (apci) m/z=523.3 (M+H).

Example 460

N-(1-(5-(3-cyano-6-((1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution ofN-(1-(5-(6-(azetidin-3-ylmethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Example 459, 46 mg, 0.088 mmol) in DCM (1.760 mL) was addedformaldehyde (0.066 mL, 0.88 mmol) and sodium triacetoxyborohydride (93mg, 0.44 mmol). The reaction mixture was stirred at rt for 1 h thenconcentrated in vacuo. The resultant crude residue was directly purifiedby C-18 reverse phase chromatography (5-95% ACN in water [+0.1% TFA] asthe gradient eluent). The fractions containing the desired product werediluted with 4:1 DCM/IPA and washed with saturated NaHCO_(3(aq)) andsaturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (9.4 mg, 0.017 mmol, 20% yield) in sufficient purity for step2. MS (apci) m/z=537.3 (M+H).

Example 461

N-(1-(5-(3-cyano-6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl(2-((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate.To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P90, 40 mg, 0.088 mmol) in DMA (0.882 mL) was added2-(Boc-amino)ethyl bromide (20 mg, 0.088 mmol) and cesium carbonate (144mg, 0.44 mmol). The reaction mixture was stirred at 70° C. for 3 h.After cooling to ambient temperature, the reaction mixture was dilutedwith 4:1 DCM/IPA and washed successively with water and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),filtered, concentrated in vacuo, and purified by C-18 reverse phasechromatography (5-95% ACN in water [+0.1% TFA] as the gradient eluent).The fractions containing the desired product were diluted with 4:1DCM/IPA and washed with saturated NaHCO_(3(aq)) and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound(assumed theoretical yield, 53 mg, 0.088 mmol) in sufficient purity forstep 2. MS (apci) m/z=597.3 (M+H).

Step 2: Preparation ofN-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

A solution of tert-butyl(2-((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)carbamate(53 mg, 0.089 mmol) in 1:1 (v/v) mixture of DCM:TFA (0.89 mL) wasstirred at rt for 16 h. The reaction mixture was diluted with 4:1DCM/IPA and washed successively with saturated NaHCO_(3(aq)) and brine.The organic extract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (34 mg, 0.068 mmol,77% yield over two steps) in sufficient purity for step 3. MS (apci)m/z=497.2 (M+H).

Step 3: Preparation ofN-(1-(5-(3-cyano-6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide.To a solution ofN-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(34 mg, 0.0685 mmol) in DCM (1.369 mL) was added formaldehyde (0.051 mL,0.685 mmol) and sodium triacetoxyborohydride (72.6 mg, 0.342 mmol). Thereaction mixture was stirred at rt for 1 h then concentrated in vacuo.The resultant crude residue was directly purified by C-18 reverse phasechromatography (5-95% ACN in water [+0.1% TFA] as the gradient eluent).The fractions containing the desired product were diluted with 4:1DCM/IPA and washed with saturated NaHCO_(3(aq)) and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The resultant film was trituratedwith DCM/hexanes and concentrated in vacuo to afford the title compound(10.5 mg, 0.0198 mmol, 29% yield). MS (apci) m/z=525.3 (M+H).

Example 462

N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl3-(((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate.To a solution ofN-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P90, 40 mg, 0.088 mmol) in DMA (0.882 mL) was added1-boc-3-bromomethyl-azetidine (24 mg, 0.088 mmol) and cesium carbonate(144 mg, 0.44 mmol). The reaction mixture was stirred at 60° C. for 16h. After cooling to ambient temperature, the reaction mixture wasdiluted with 4:1 DCM/IPA and washed successively with water andsaturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, concentrated in vacuo, and purified by C-18reverse phase chromatography (5-95% ACN in water [+0.1% TFA] as thegradient eluent). The fractions containing the desired product werediluted with 4:1 DCM/IPA and washed with saturated NaHCO_(3(aq)) andsaturated NaCl_((aq)). The organic extract was dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (54 mg, 0.084 mmol, 96% yield) in sufficient purity for step 2.MS (apci) m/z=641.3 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide.A solution of tert-butyl3-(((3-cyano-4-(6-(4-methyl-4-(picolinamido)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(54 mg, 0.084 mmol) in 1:1 (v/v) mixture of DCM:TFA (0.84 mL) wasstirred at rt for 1 h. The reaction mixture was diluted with 4:1 DCM/IPAand washed successively with saturated NaHCO_(3(aq)) and brine. Theorganic extract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The residue was purified by C-18 reverse phasechromatography (5-95% ACN in water [+0.1% TFA] as the gradient eluent).The fractions containing the desired product were diluted with 4:1DCM/IPA and washed with saturated NaHCO_(3(aq)) and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (5.0mg, 11% yield). MS (apci) m/z=541.2 (M+H).

Example 463

N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution ofN-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Example 462, 35 mg, 0.065 mmol) in DCM (1.295 mL) was addedformaldehyde (0.048 mL, 0.65 mmol) and sodium triacetoxyborohydride (69mg, 0.32 mmol). The reaction mixture was stirred at rt for 1 h. Thereaction mixture was concentrated in vacuo, and the resultant cruderesidue was directly purified by C-18 reverse phase chromatography(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were diluted with 4:1 DCM/IPA and washedwith saturated NaHCO_(3(aq)) and saturated NaCl_((aq)). The organicextract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (19 mg, 0.034 mmol,53% yield). MS (apci) m/z=555.3 (M+H).

Example 464

N-(1-(5-(6-(2-(4-acetylpiperazin-1-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P91, 35 mg, 0.0619 mmol) in DCM (0.619 mL) was added TEA(0.00862 mL, 0.0619 mmol) and acetyl chloride (0.124 mL, 0.124 mmol).The reaction mixture was stirred at rt for 1 h. The reaction mixture wasdiluted with 4:1 DCM/IPA and washed successively with water and brine.The organic extract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The residue was purified by C-18 reverse phasechromatography (5-95% ACN in water [+0.1% TFA] as the gradient eluent).The fractions containing the desired product were diluted with 4:1DCM/IPA and washed with saturated NaHCO_(3(aq)) and saturatedNaCl_((aq)). The organic extract was dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (27.7mg, 0.0456 mmol, 73.7% yield). MS (apci) m/z=608.3 (M+H).

Example 465

N-(1-(5-(3-cyano-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution ofN-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P91, 40 mg, 0.0707 mmol) in DCM (1.414 mL) was addedformaldehyde (0.0526 mL, 0.707 mmol) and sodium triacetoxyborohydride(74.9 mg, 0.354 mmol). The reaction mixture was stirred at rt for 1 h.The reaction mixture was concentrated in vacuo, and the resultant cruderesidue was directly purified by C-18 reverse phase chromatography(5-95% ACN in water [+0.1% TFA] as the gradient eluent). The fractionscontaining the desired product were diluted with 4:1 DCM/IPA and washedwith saturated NaHCO_(3(aq)) and saturated NaCl_((aq)). The organicextract was dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(0-10% MeOH in DCM as the gradient eluent) to afford the title compound(15.4 mg, 37.6% yield). MS (apci) m/z=580.3 (M+H).

Example 466

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropyl-4-methylpiperidine-4-carboxamide

To a solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid (Intermediate P92, 38.2 mg, 0.0942 mmol) in DCM (0.942 mL) wasadded HATU (43.0 mg, 0.113 mmol), DIEA (0.033 mL, 0.188 mmol), andpropan-2-amine (0.009 mL, 0.104 mmol). The reaction mixture was stirredat rt for 16 h. The reaction mixture was concentrated in vacuo, and theresultant crude residue was directly purified by C-18 reverse phasechromatography (5-95% ACN in water [+2% TFA] as the gradient eluent).The fractions containing the desired product were diluted with 4:1DCM/IPA and washed with saturated NaHCO_(3(aq)). The organic extract wasdried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto afford the title compound (32.4 mg, 0.0726 mmol, 77% yield). MS(apci) m/z=447.2 (M+H).

The compounds in Table FFF were prepared using a similar method to thatdescribed for the synthesis of Example 466, replacing propan-2-aminewith the appropriate amine coupling partner. Reactions were monitoredfor completion by LCMS, and reaction durations were adjustedaccordingly. Title compounds were cleanly isolated followingchromatographic purification using an appropriate gradient eluent (andif necessary converted to the free base).

TABLE FFF MS Ex. # Structure Chemical Name m/z 467

6-ethoxy-4-(6-(4-methyl- 4-(pyrrolidine-1- carbonyl)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 459.25 (M + H)468

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4- methylpiperidine-4- carboxamide 461.25 (M + H) 469

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin- 3-yl)-4-methylpiperidine- 4-carboxamide 512.20(M + H) 470

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(pyridin-3- yl)piperidine-4- carboxamide 482.20 (M + H)471

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(6- methylpyridin-3- yl)piperidine-4- carboxamide 496.20(M + H) 472

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(5- methylpyridin-2- yl)piperidine-4- carboxamide 496.20(M + H) 473

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(pyridin-2- yl)piperidine-4- carboxamide 482.20 (M + H)474

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2- yl)-N-(cyclopropylmethyl)-4- methylpiperidine-4- carboxamide 459.20 (M + H)475

(R)-1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3- methylbutan-2- yl)piperidine-4- carboxamide 475.30(M + H) 476

(S)-1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3- methylbutan-2- yl)piperidine-4- carboxamide 475.30(M + H) 477

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(2,2,2- trifluoroethyl)piperidine-4- carboxamide 487.20(M + H) 478

(S)-1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N-(2-hydroxypropyl)- 4-methylpiperidine-4- carboxamide 463.20 (M +H)

Example 479

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate.A solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 2.535 g, 7.768 mmol) in DMSO (6.1 mL) was treatedsequentially with tert-butyl (4-methylpiperidin-4-yl)carbamate (1.998mg, 9.322 mmol) and DIEA (4.06 mL, 23.3 mmol). The resulting mixturestirred overnight at 90° C. After cooling to ambient temperature, thereaction mixture was poured into 80 mL water and diluted with 80 mLheptane and stirred for 1 hour. The suspension was filtered and thesolids were rinsed with 25 mL water then 25 mL heptane. The isolatedsolids were dried under vacuum for 18 hours to afford the title compound(4.04 g, 99.9% yield) in sufficient purity for step 2. MS (apci)m/z=521.3 (M+H)

Step 2: Preparation of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. A solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(4.04 g, 7.76 mmol) in DCM (20 mL) was cooled to 0° C. The reaction wastreated with TFA (5.98 mL) and allowed to warm to RT. After stirring for30 min at ambient the reaction mixture was concentrated in vacuo. Theresidue was dissolved in MeOH (20 mL) and cooled to 0° C. and thentreated with Hydrochloric acid, 5 to 6N solution in 2-propanol (15.5 mL,77.5 mmol) and stirred for 15 min at 0° C. The reaction was diluted with20 mL MTBE, filtered, and solids were rinsed with 20 mL 1:1 MTBE: MeOH.The isolated solids were dried under vacuum to cleanly provide the titlecompound (3.37 g, 88% yield). MS (apci) m/z=421.2 (M+H).

Example 480

6-ethoxy-4-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 0.500 g, 1.77 mmol) in DMSO (3.5 mL) was added TEA(0.741 mL, 5.31 mmol) and piperidin-4-ol (269 mg, 2.66 mmol). Thereaction mixture was stirred at 70° C. for 5 h. After cooling to ambienttemperature, the reaction mixture was poured into ice water. Theresultant solids were isolated by vacuum filtration to afford the titlecompound (501 mg, 1.38 mmol, 77.8% yield). MS (apci) m/z=364.2 (M+H).

Example 481

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-(pyridin-2-ylthio)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 210 mg, 0.64 mmol) and2-(piperidin-4-ylsulfanyl)pyridine (357 mg, 1.84 mmol) in DMA (1.6 mL)was added TEA (628 μL, 4.50 mmol). The reaction mixture was stirredovernight at 95° C. After cooling to ambient temperature, the reactionmixture was diluted water and extracted with EtOAc. The organic extractswere washed with water and brine. The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The residuewas purified by silica chromatography (10-90% EtOAc in Hexanes to affordthe title compound (20 mg, 61% yield). MS (apci) m/z=501.2 (M+H).

Example 482

Step 1: Preparation of tert-butyl((1R,5S,6r)-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 200 mg, 0.57 mmol) and tert-butyl((1R,5S,6r)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate(169 mg, 0.80 mmol)in DMSO (0.57 mL) was added DIEA (298 μL, 1.71 mmol). The reactionmixture was stirred overnight under a N_(2(g)) atmosphere at 90° C.After cooling to ambient temperature, the reaction mixture was dilutedwith water (5.7 mL). The suspension was filtered and the solids wererinsed with water (3×5 mL) then MTBE (3×5 mL). The isolated solids weredried under vacuum while the MTBE filtrate was concentrated in vacuo.The filtrate residue was purified by C18 reverse phase chromatography(5-50% ACN in water). The precipitate solids and chromatography productwere combined and concentrated in vacuo to cleanly provide the titlecompound (292 mg, 98% yield) in sufficient purity for step 2. MS (apci)m/z=519.20 (M+H).

Example 483

4-(6-((1R,5S,6r)-6-amino-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileDihydrochloride

To a solution of tert-butyl((1R,5S,6r)-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)carbamate(Example 507A; 148 mg, 0.29 mmol) in MeOH (571 μL) was added HCl (conc.)(476 μL, 5.71 mmol) dropwise. The reaction was stirred for 2 h atambient temperature. The reaction was diluted with EtOAc (1 mL) and wasstirred at ambient temperature for 10 minutes. MTBE (1 mL) was added anda suspension formed. The suspension was filtered and solids were rinsedwith 10% MeOH in MTBE (3×1 mL) to cleanly provide the title compound(114 mg, 81% yield). MS (apci) m/z=419.15 (M+H).

Example 484

4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: Preparation of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate.To a solution of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 205 mg, 0.628 mmol) and tert-butylpiperidin-4-ylcarbamate (252 mg, 1.26 mmol) in DMA (2.09 mL) was addedDIEA (549 μL, 3.14 mmol). The reaction was stirred 2 h at 95° C. Aftercooling to ambient temperature, the reaction mixture was diluted withwater and extracted with EtOAc. The organic extracts were washed withwater and brine. The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (assumed quantitative yield, 319 mg) in sufficient purity forstep 2. MS (apci) m/z=507.20 (M+H)

Step 2: Preparation of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of tert-butyl(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate(319 mg, 0.63 mmol) in DCM (3.15 mL) was added TFA (3.14 mL, 40.9 mmol).The reaction was stirred for 30 min at ambient temperature. The reactionwas concentrated in vacuo. The residue was resuspended in DCM andpurified using silica chromatography (1-9% MeOH in DCM with 0.1-0.9%NH₄OH as the gradient eluent) to cleanly provide the title compound (37mg, 53% yield) MS (apci) m/z=407.2 (M+H).

Example 485

N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P67; 503 mg, 1.19 mmol),5-fluoro-2-methylbenzoic acid (552 mg, 3.58 mmol), and HATU (1.36 g,3.58 mmol) in DMSO (5 mL) was added DIEA (1.7 mL, 9.55 mmol). Thereaction was stirred 16 h at ambient temperature. The reaction mixturewas diluted with THF (4 mL) and treated with NaOH (5.97 mL, 11.9 mmol)and stirred for 4 h at ambient temperature. The reaction wasconcentrated in vacuo. The residue was diluted with EtOAc and washedwith water. The pH was adjusted to pH 5 with AcOH and then extractedwith EtOAc. The organic extracts were washed with brine. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was purified using silicachromatography (50-100% Hexanes to EtOAc) to afford the title compound(534 mg, 92% yield) in sufficient purity for step 2. MS (apci) m/z=485.2(M+H).

Example 486

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Example 446, 100 mg, 0.210 mmol) in DCM (2 mL) was treated with TFA (2mL). The reaction mixture was stirred at rt for 1 h. The crude reactionmixture was directly purified by silica chromatography (5-50% [MeOH+2%NH₄OH] in DCM as the gradient eluent) to afford the title compound (20mg, 0.0531 mmol, 25.3% yield). MS (apci) m/z=377.2 (M+H).

Example 487

3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P67; 256 mg, 0.608 mmol),3-Chloropicolinic acid (287 mg, 1.82 mmol), and HATU (294 mg, 1.82 mmol)in DMSO (3 mL) was added DIEA (0.74 mL, 4.25 mmol). The reaction wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with EtOAc (10 mL) and washed with water (10 mL) and4:1AcOH:water (10 mL) and then extracted with EtOAc. The organicextracts were washed with 4:1 AcOH:Water and then brine. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The residue was diluted with THF (4 mL) and 2MNaOH (6 mL). The solution was concentrated in vacuo. The residue wasresuspended in DCM (2 mL) and purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA as the gradient eluent)to afford the title compound as the TFA salt. The TFA salt wasresuspended in DCM and passed through a Pl-HCO₃ resin to elute thefree-based product. The organic eluents were concentrated in vacuo andrecrystallized using DCM/Hexanes to afford the title compound (226 mg,76% yield). MS (apci) m/z=488.2 (M+H).

Example 488

4-(6-(4-((3-fluoropyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-((3-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate

To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(175 mg, 0.869 mmol) in DMF (2.2 mL) was added sodium hydride (60% w/w,41.7 mg, 1.04 mmol). The reaction was stirred for 10 min at ambienttemperature. 2,3-Difluoropyridine (100 mg, 0.869 mmol) was added andreaction stirred overnight at 60° C. The reaction was cooled to ambienttemperature and diluted with DCM and washed with saturatedNaHCO_(3(aq)), water, and brine. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (assumed quantitative yield, 258 mg) insufficient purity for step 2. MS (apci) m/z=197.2 (M−Boc).

Step 2: Preparation of 3-fluoro-2-(piperidin-4-yloxy)pyridineHydrochloride

To a solution of tert-butyl4-((3-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate (assumed 258 mg,0.869 mmol) in 4.3 mL DCM was treated with TFA (4.3 mL, 55.8 mmol). Thereaction mixture was stirred for 1 h at ambient temperature, and thenconcentrated in vacuo. The crude residue was resuspended in MeOH andtreated with treated with 4 N HCl in dioxanes (4 mL). The solution wasstirred at ambient temperature for 15 min. The reaction was concentratedin vacuo to provide the title compound as a dihydrochloride salt, whichwas used in the next step without further purifications. MS (apci)m/z=197.1 (M+H).

Step 3: Preparation of4-(6-(4-((3-fluoropyridin-2-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.To a mixture of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42; 40 mg, 0.123 mmol) and3-fluoro-2-(piperidin-4-yloxy)pyridine dihydrochloride (66 mg, 0.245mmol) in DMA (0.817 mL) was added TEA (103 μL, 0.735 mmol). The reactionmixture was stirred overnight at 95° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM and washed withwater and brine. The organic extracts were dried over anhydrousNa₂SO₄(s), filtered and concentrated in vacuo. The residue was purifiedby C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was treated with saturated Na₂CO_(3(aq)) and extracted withDCM. The combined organic extracts were washed with brine, then driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo toafford the title compound (17 mg, 28% yield). MS (apci) m/z=503.2 (M+H).

Example 489

1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-4-sulfonamide

A mixture of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P93; 31.8 mg, 0.119 mmol),N-isopropylpiperidine-4-sulfonamide (Intermediate R18; 45 mg, 0.218mmol) and DIEA (62.1 μL, 0.356 mmol) in DMSO (500 μL) was stirred for 2d at 90° C. After cooling to ambient temperature, the mixture wasdiluted with water, cooled to 0° C., and the resultant suspension wasfiltered. The solids were rinsed with water, and purified by silicachromatography (using 30-100% Hexanes/EtOAc as the gradient eluent) toafford the title compound (11.5 mg, 21% yield). MS (apci) m/z=455.15(M+H).

Example 490

trans-tert-butyl1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methoxypiperidin-4-yl)carbamate

A mixture of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P93; 201.7 mg, 0.7519 mmol), tert-butyl(3-methoxypiperidin-4-yl)carbamate (mixture of trans isomers) (259.8 mg,1.128 mmol) and DIEA (394.0 μL, 2.256 mmol) in DMSO (3 mL) was stirredovernight at 90° C. After cooling to ambient temperature, the mixturewas diluted with water, and cooled to 0° C. The resultant suspension wasfiltered, and the solids were rinsed with cold water (3×), and purifiedby silica chromatography (using 30-70% Hexanes/EtOAc as the gradienteluent) to afford the title compound (299.8 mg, 83% yield). MS (apci)m/z=479.2 (M+H).

Example 491

tert-butyl((3S,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate

A solution of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P93; 158.5 mg, 0.5909 mmol), and tert-butyl((3S,4S)-3-hydroxypiperidin-4-yl)carbamate (216.3 mg, 1.000 mmol) inDMSO (2 mL) was treated with DIEA (516.0 μL, 2.954 mmol), then stirredovernight at 100° C. After cooling to ambient temperature, the mixturewas diluted with water, and the resultant suspension was filtered. Thesolids were rinsed with water (3×), then dried in vacuo to cleanlyafford the title compound (335.8 mg, quantitative yield). MS (apci)m/z=465.2 (M+H).

Example 492

N-((3S,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide

A solution of4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P94; 50 mg, 0.11 mmol) and DIEA (120 μL,0.69 mmol) in DCM (2 mL) was cooled to 0° C., then treated withisovaleryl chloride (33 μL, 0.27 mmol). The resulting mixture wasstirred for 10 min at 0° C., and then for 2 h at ambient temperature.The reaction mixture was purified by silica chromatography (using20-100% EtOAc in Hexanes as the gradient eluent), then again by C18reverse phase chromatography (using 20-80% ACN in water with 0.1% TFA asthe gradient eluent) to cleanly provide the title compound as the TFAsalt. The TFA salt was partitioned between saturated NaHCO_(3(aq)) and4:1 DCM:iPrOH, and passed through a PS Frit. The organic extracts wereconcentrated in vacuo to cleanly afford the title compound (2.0 mg, 3%yield). MS (apci) m/z=449.2 (M+H).

Example 493

N-((3S,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-1-(trifluoromethyl)cyclobutane-1-carboxamide

A solution of4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P94; 50 mg, 0.11 mmol) and DIEA (120 μL,0.686 mmol) in DCM (2 mL) was treated sequentially with1-(trifluoromethyl)cyclobutane-1-carboxylic acid (46.1 mg, 0.274 mmol)and HATU(104 mg, 0.274 mmol), then stirred for 1.5 h at ambienttemperature. The resulting mixture was purified directly by silicachromatography (using 20-100% EtOAc in Hexanes as the gradient eluent)to cleanly provide the title compound (18.4 mg, 26% yield). MS (apci)m/z=515.2 (M+H).

The compounds in Table GGG were prepared using a similar method to thatdescribed in the synthesis ofN-((3S,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-1-(trifluoromethyl)cyclobutane-1-carboxamide(Example 493) replacing 1-(trifluoromethyl)cyclobutane-1-carboxylic acidwith the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.The title compounds were isolated following a chromatographicpurification utilizing an appropriate gradient eluent.

TABLE GGG MS (apci) Ex # Structure Chemical Name m/z 494

N-((3S,4S)-1-(5-(3-cyano- 6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4-yl)-1-methylcyclobutane-1- carboxamide 461.3 (M + H) 495

N-((3S,4S)-1-(5-(3-cyano- 6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4-yl)-1-(trifluoromethyl)cyclopropane- 1-carboxamide 501.2 (M + H) 496

N-((3S,4S)-1-(5-(3-cyano- 6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4-yl)-2,3-dimethylbutanamide 463.2 (M + H)

Example 497

Isopropyl(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A mixture of4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P93; 26.5 mg, 0.0988 mmol), isopropyl(4-methylpiperidin-4-yl)carbamate hydrochloride (Intermediate R19, partB; 72.3 mg, 0.305 mmol) and Cs₂CO_(3(s)) (322 mg, 0.988 mmol) in DMSO(1.5 mL) was stirred overnight at 100° C. The reaction mixture wascooled to ambient temperature. The incomplete reaction mixture wastreated with additional isopropyl (4-methylpiperidin-4-yl)carbamatehydrochloride (72.3 mg, 0.305 mmol) and a few drops of DIEA. Afterstirring for 6 d at ambient temperature, the reaction mixture wasdiluted with water and extracted with additional DCM (4×). The combinedDCM extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The resulting crude residue was purified bysilica chromatography (using 0-100% Hexanes/EtOAc as the gradienteluent) to cleanly afford the title compound (5.1 mg, 12% yield). MS(apci) m/z=449.2 (M+H).

Example 498

3-chloro-6-methoxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

In a pressure vessel, a mixture of3-chloro-4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine(Example 417, Step 2; 30 mg, 0.11 mmol), 2-(piperidin-4-yloxy)pyridine(29 mg, 0.16 mmol) and Cs₂CO_(3(s)) (176 mg, 0.54 mmol) in DMSO (200 μL)was stirred overnight at 90° C. After cooling to ambient temperature,the reaction mixture was poured into 2N NaOH_((aq)) (2 mL), andextracted with 10% iPrOH in DCM (2×3 mL) in a PS Frit. The combinedorganic extracts were concentrated in vacuo. The resulting crude residuewas purified by silica chromatography (using 0-100% EtOAc/Hexanes as thegradient eluent) to cleanly afford the title compound (22 mg, 47%yield). MS (apci) m/z=436.1 (M+H).

Example 499

Isopropyl(1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A mixture of3-chloro-4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine(Example 417, Step 2; 26.5 mg, 0.0954 mmol), isopropyl(4-methylpiperidin-4-yl)carbamate hydrochloride (Intermediate R19; 70.9mg, 0.299 mmol) and Cs₂CO_(3(s)) (311 mg, 0.954 mmol) in DMSO (3 mL) wasstirred overnight at 100° C. The reaction mixture was cooled to ambienttemperature. The incomplete reaction mixture was treated with additionalisopropyl (4-methylpiperidin-4-yl)carbamate hydrochloride (IntermediateR19, part B; 70.9 mg, 0.299 mmol) and a few drops of DIEA. Afterstirring for 6 d at ambient temperature, the reaction mixture waspartitioned between water and DCM then extracted with additional DCM(3×). The DCM extracts were combined, dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The resulting crude residue waspurified by silica chromatography (using 0-100% Hexanes/EtOAc as thegradient eluent) to cleanly afford the title compound (1.8 mg, 3%yield). MS (apci) m/z=458.15 (M+H).

Example 500

N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)-3-methylbutanamide

A solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 176.2 mg, 0.6242 mmol), andN-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methylbutanamide hydrochloride(Intermediate R21; 270 mg, 1.212 mmol) in DMSO (1.5 mL) was treated withDIEA (545.1 μL, 3.121 mmol). The reaction mixture was stirred overnightat 90° C., then cooled to ambient temperature, and diluted with water.The resultant suspension was filtered, and the solids were rinsed withwater (3×), then dried in vacuo. The crude solids were purified by C18reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA asthe gradient eluent) to afford the title compound as the TFA salt. TheTFA salt was suspended in MeOH, eluted through a basic resin(Stratospheres MP-HCO3) to cleanly afford the title compound (5.5 mg,77% yield). MS (apci) m/z=449.2 (M+H).

The compounds in Table HHH were prepared using a similar method to thatdescribed for the preparation, isolation and purification ofN-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)-3-methylbutanamide(Example 500), replacing theN-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methylbutanamide hydrochloridewith the appropriate commercial pyrrolidine. Reactions were monitoredfor completion by LCMS. And reaction durations were adjustedaccordingly.

TABLE HHH MS (apci) Ex # Structure Chemical Name m/z 501

tert-butyl ((3R,4S)-1- (5-(3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4- hydroxypyrrolidin-3- yl)carbamate 465.2(M + H) 502

tert-butyl ((3S,4R)-1- (5-(3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4- hydroxypyrrolidin-3- yl)carbamate 465.2(M + H)

Example 503

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-((trans)-4-methoxypyrrolidin-3-yl)-3-methylbutanamideStep 1: Preparation of4-(6-((trans)-3-amino-4-methoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 252.1 mg, 0.8931 mmol) in DMSO (4.5 mL) was treatedwith tert-butyl ((3R,4R)-4-methoxypyrrolidin-3-yl)carbamate (386.3 mg,1.786 mmol) and DIEA (311.1 μL, 1.786 mmol). The reaction mixture wasstirred for 1 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc, washed with water (3×) andbrine (1×). The organic extracts were dried over Na₂SO_(4(s)), thenfiltered, and concentrated in vacuo. The crude residue was dissolved in1:1 DCM:TFA (4.5 mL), stirred for 30 min at ambient temperature, andsubsequently concentrated in vacuo. The residue was purified by C18reverse phase chromatography (5-95% ACN in water with 0.1% TFA).Fractions containing the desired compound were combined, and partitionedbetween 4:1 DCM:iPrOH and saturated NaHCO_(3(aq)). The organic extractswere dried over anhydrous Na₂SO_(4(s)), filtered, and concentrated invacuo to afford the title compound (125.8 mg, 37% yield). MS (apci)m/z=379.2 (M+H).

Step 2: Preparation ofN-((trans)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methoxypyrrolidin-3-yl)-3-methylbutanamide.A solution of4-(6-((trans)-3-amino-4-methoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(46.0 mg, 0.122 mmol) in DCM (1.2 mL) was treated with isovalerylchloride (29.6 μL, 0.243 mmol) and TEA (84.7 μL, 0.608 mmol), thenstirred for 16 h at ambient temperature. The reaction mixture wasdirectly purified by silica chromatography (using 5-60% DCM-Acetone asthe gradient eluent) to cleanly provide the title compound (45.6 mg, 81%yield). MS (apci) m/z=463.3 (M+H).

Example 504

N-((trans)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methoxypyrrolidin-3-yl)benzamide

A solution of4-(6-((trans)-3-amino-4-methoxypyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 503, step 1: 46.5 mg, 0.1229 mmol) in DCM (1.2 mL) was treatedwith benzoyl chloride (28.53 μL, 0.2457 mmol) and TEA (85.63 μL, 0.6144mmol), then stirred for 16 h at ambient temperature. The reactionmixture was directly purified by silica chromatography (using 5-60%DCM-Acetone as the gradient eluent) to cleanly provide the titlecompound (45.6 mg, 81% yield). MS (apci) m/z=483.3 (M+H).

Example 505

N-((3S,4S)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide

Step 1: Preparation of tert-butyl((3S,4S)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate.A mixture of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P61, 49.1 mg, 0.106 mmol), DIAD (41.1 μL, 0.211 mmol),diphenyl phosphorazidate (58.2 mg, 0.211 mmol) and PPh₃ (55.4 mg, 0.211mmol) in THF (1 mL) was stirred overnight at ambient temperature. Thereaction mixture was concentrated in vacuo, and purified by silicachromatography (using 0-70% EtOAc in Hexanes as the gradient eluent) tocleanly afford the title compound (51 mg, 99% yield). MS (apci)m/z=448.2 (M+H).

Step 2: Preparation of4-(6-((3S,4S)-3-amino-4-azidopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. A solution of tert-butyl ((3S,4S)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(51 mg, 0.10 mmol) in dioxane (1.0 mL) was treated with conc. HCl_((aq))(6.3 μL, 0.21 mmol). The resulting mixture was stirred overnight atambient temperature before concentrating the mixture in vacuo to affordthe title compound (48 mg, 100% yield). MS (apci) m/z=390.15 (M+H).

Step 3: Preparation ofN-((3S,4S)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide.A 0° C. solution of4-(6-((3S,4S)-3-amino-4-azidopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (48 mg, 0.104 mmol) and DIEA (90.7 μL, 0.519 mmol) inDCM (1 mL) was treated dropwise with isovaleryl chloride (15.2 μL, 0.125mmol). The cooling bath was removed, and resulting mixture was stirredovernight at ambient temperature. The reaction mixture was diluted withDCM, and washed with water. The organic extracts were directly purifiedby silica chromatography (using 20-80% EtOAc in Hexanes as the gradienteluent) to cleanly provide the title compound (40.1 mg, 82% yield). MS(apci) m/z=474.2 (M+H).

Step 4: Preparation ofN-((3S,4S)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide.A solution ofN-((3S,4S)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide(40.1 mg, 0.0847 mmol) and PPh₃ (44.4 mg, 0.169 mmol) in THF (1 mL) wasstirred at for 30 min at ambient temperature. The resulting mixture wasdiluted with water (0.1 mL, 0.0847 mmol), then stirred for 2 h atambient temperature. Subsequently, additional water (0.1 mL, 0.0847mmol) was introduced, and the reaction mixture was stirred overnight atambient temperature. As the reaction remained incomplete, additionalwater (0.1 mL, 0.0847 mmol) was introduced, and the mixture was stirredovernight at 55° C. After cooling to ambient temperature, the mixturewas concentrated in vacuo. The residue was purified by C18 reverse phasechromatography (using 5-95% water-ACN with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wassuspended in MeOH and filtered through a basic resin (StratospheresMP-HCO3). The filtrate was concentrated in vacuo to cleanly afford thetitle compound (5.5 mg, 14% yield). MS (apci) m/z=448.2 (M+H).

Example 506

N-((3R,4R)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide

Step 1: Preparation of tert-butyl((3R,4R)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate.A mixture of tert-butyl((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamate(Intermediate P60, 52.9 mg, 0.114 mmol), DIAD (44.3 μL, 0.228 mmol),diphenyl phosphorazidate (62.7 mg, 0.228 mmol) and PPh₃ (59.7 mg, 0.228mmol) in THF (1 mL) was stirred overnight at ambient temperature. Thereaction mixture was concentrated in vacuo, and purified by silicachromatography (using 0-70% EtOAc in Hexanes as the gradient eluent) tocleanly afford the title compound (55 mg, 99% yield). MS (apci)m/z=490.2 (M+H).

Step 2: Preparation of4-(6-((3R,4R)-3-amino-4-azidopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. A solution of tert-butyl((3R,4R)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(55 mg, 0.11 mmol) in dioxane (1.0 mL) was treated with 12 M HCl_((aq))(6.8 μL, 0.22 mmol). The resulting mixture was stirred overnight atambient temperature before concentrating the mixture in vacuo to affordthe title compound (52 mg, 100% yield). MS (apci) m/z=390.1 (M+H).

Step 3: Preparation ofN-((3R,4R)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide.A cold (0° C.) solution of4-(6-((3R,4R)-3-amino-4-azidopyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (52 mg, 0.112 mmol) and DIEA (98.2 μL, 0.562 mmol) inDCM (1 mL) was treated dropwise with isovaleryl chloride (16.5 μL, 0.135mmol). The cooling bath was removed, and resulting mixture was stirredovernight at ambient temperature. The reaction mixture was diluted withDCM, and washed with water. The organic extracts were directly purifiedby silica chromatography (using 20-80% EtOAc in Hexanes as the gradienteluent) to cleanly provide the title compound (55.3 mg, quantitativeyield). MS (apci) m/z=474.2 (M+H).

Step 4: Preparation ofN-((3R,4R)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide.A solution ofN-((3R,4R)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)-3-methylbutanamide(55.3 mg, 0.117 mmol) and PPh₃ (61.3 mg, 0.234 mmol) in THF (9.57 μL)was stirred at for 30 min at ambient temperature. The resulting mixturewas diluted with water (2.10 μL, 0.117 mmol), then stirred for 2 h atambient temperature. As the reaction remained incomplete, additionalwater (2.10 μL, 0.117 mmol) was introduced, and the mixture was stirredfor 5 d at 55° C. After cooling to ambient temperature, the mixture wasconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (using 5-95% water-ACN with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wassuspended in MeOH and filtered through a basic resin (StratospheresMP-HCO3). The filtrate was concentrated in vacuo to cleanly afford thetitle compound (5.2 mg, 10% yield). MS (apci) m/z=448.2 (M+H).

Example 507

Ethyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

A mixture of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 103.4 mg, 0.3663 mmol), ethyl piperidine-4-carboxylatehydrochloride (Intermediate R22; 242.3 mg, 1.251 mmol) and TEA (510.6μL, 3.663 mmol) in DMSO (3 mL) was stirred for 6 d at 60° C. Thereaction mixture was cooled to ambient temperature, and partitionedbetween water and DCM. The resulting biphasic mixture was extracted withDCM (3×) and then with 4:1 DCM/iPrOH. The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The resulting crude residue was purified by silica chromatography (using0-25% DCM/MeOH as the gradient eluent) to cleanly afford the titlecompound (66.3 mg, 41% yield). MS (apci) m/z=420.2 (M+H).

Example 508

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-ylIsopropylcarbamate

A solution of 2-isocyanatopropane (50.5 mg, 0.593 mmol) in DCM (1 mL)and 12 M HCl_((aq)) (0.1 mL, 0.0825 mmol) was added to6-ethoxy-4-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P52, 30 mg, 0.0825 mmol). After stirring overnight atambient temperature, the reaction mixture was purified directly bysilica chromatography (using 20-80% Hexanes/EtOAc as the gradienteluent) to cleanly provide the title compound (6.0 mg, 16% yield). MS(apci) m/z=449.2 (M+H).

Example 509

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-4-sulfonamide

A mixture of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 32.1 mg, 0.114 mmol),N-isopropylpiperidine-4-sulfonamide (Intermediate R18; 45 mg, 0.218mmol) and DIEA (59.6 μL, 0.341 mmol) in DMSO (500 μL) was stirred for 2d at 90° C. After cooling to ambient temperature, the mixture wasdiluted with water, cooled to 0° C., and the resultant suspension wasfiltered. The solids were rinsed with water, and purified by silicachromatography (using 30-100% Hexanes/EtOAc as the gradient eluent) toafford the title compound (9.8 mg, 16% yield). MS (apci) m/z=469.2(M+H).

Example 510

trans-tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-((3-methoxypiperidin-4-yl)carbamate

A mixture of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 106.1 mg, 0.3759 mmol), tert-butyl(3-methoxypiperidin-4-yl)carbamate (mixture of trans isomers) (173.1 mg,0.7517 mmol), and Cs₂CO_(3(s)) (612.3 mg, 1.879 mmol) in DMSO (2.0 mL)was stirred for 4 d at 60° C. The reaction mixture was cooled to ambienttemperature, and diluted with water. The resulting suspension wasfiltered, and the solids were rinsed with water. The crude solid waspurified by silica chromatography (using 20-60% Hexanes/EtOAc as thegradient eluent) to cleanly afford the title compound (154 mg, 83%yield). MS (apci) m/z=493.2 (M+H).

Example 511

trans-4-(6-((3R,4R)-4-amino-3-methoxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methoxypiperidin-4-yl)carbamate(Example 510; 181 mg, 0.367 mmol) was suspended in DCM (3 mL) andtreated with TFA (1.5 mL, 19 mmol). The resulting mixture was stirredfor 1 h at ambient temperature before concentrating the mixture invacuo. The crude residue was partitioned between DCM and saturatedNaHCO_(3(aq)) then extracted with 4:1 DCM:iPrOH (3×), then with EtOAc.The combined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo to afford the title compound (45.4mg, 32% yield). MS (apci) m/z=393.2 (M+H).

Example 512

tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate

A solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 177.8 mg, 0.6299 mmol) and tert-butyl((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (199 mg, 0.9201 mmol) in DMSO(1.5 mL) was treated with DIEA (55.01 μL, 3.149 mmol), and stirred for 2d at 90° C. After cooling to ambient temperature, the mixture wasdiluted with water, and the resultant suspension was filtered. Thesolids were rinsed with water (3×), then dried in vacuo to afford thetitle compound (255.2 mg, 81% yield). MS (apci) m/z=479.2 (M+H).

The compounds in Table III were prepared using a similar method to thatdescribed for the preparation, isolation and purification of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 512), replacing the tert-butyl((3R,4R)-3-hydroxypiperidin-4-yl)carbamate with the appropriatecommercial piperidine. Reactions were conducted at 90-95° C., andmonitored for completion by LCMS. And reaction durations were adjustedaccordingly.

TABLE III MS (apci) Ex # Structure Chemical Name m/z 513

tert-butyl ((3S,4S)-1- (5-(3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3- hydroxypiperidin-4- yl)carbamate 479.2(M + H) 514

tert-butyl ((3R,4S)-1- (5-(3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3- hydroxypiperidin-4- yl)carbamate 479.2(M + H) 515

tert-butyl ((3S,4R)-1- (5-(3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-3- hydroxypiperidin-4- yl)carbamate 479.2(M + H)

Example 516

tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-(2-(dimethylamino)ethoxy)piperidin-4-yl)carbamate

A solution of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 512; 51.8 mg, 0.108 mmol) and 2-bromo-N,N-dimethylethan-1-aminehydrobromide (25.2 mg, 0.108 mmol) in DCM (1 mL) was treated with DIEA(189 μL, 1.08 mmol). After stirring overnight at ambient temperature, 5mg of NaH was introduced. The reaction was stirred for 3 d at ambienttemperature before additional 2-bromo-N,N-dimethylethan-1-aminehydrobromide (25.2 mg, 0.108 mmol) and DIEA (189 μL, 1.08 mmol) in 1 mLDCM was added. The resulting mixture was stirred overnight at ambienttemperature. The reaction mixture was diluted with DCM and washed withwater. The organic extracts were purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA) to cleanly provide thetitle compound as the TFA salt. The TFA salt was suspended in MeOH,eluted through a basic resin (Stratospheres MP-HCO3) to cleanly affordthe title compound (2.7 mg, 5% yield). MS (apci) m/z=550.2 (M+H).

Example 517

tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-(2-(dimethylamino)ethoxy)piperidin-4-yl)carbamate

The title compound was prepared, worked up and purified using a similarprocedure to that described for tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-(2-(dimethylamino)ethoxy)piperidin-4-yl)carbamate(Example 516), replacing tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 512) with tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 513). MS (apci) m/z=550.3 (M+H).

Example 518

4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 513; 174.3 mg, 0.36 mmol) in dioxane (2.0 mL) was treated with12 M HCl_((aq)) (22.13 μL, 0.7284 mmol). The resulting mixture wasstirred for 1 h at ambient temperature before concentrating the mixturein vacuo. The crude residue was dissolve in MeOH and eluted through abasic resin (Stratospheres MP-HCO3), to cleanly afford the titlecompound (137 mg, 96% yield). MS (apci) m/z=379.15 (M+H).

Example 519

N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide

A solution of4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 518; 50 mg, 0.132 mmol) and DIEA (115 μL, 0.661 mmol) in DCM (2mL) was stirred for 20 min at 0° C. The cold solution was treateddropwise with isovaleryl chloride (32.2 μL, 0.264 mmol). The resultingmixture was stirred overnight at ambient temperature. The reactionmixture was directly purified by silica chromatography (using 20-80%EtOAc in Hexanes as the gradient eluent) to cleanly provide the titlecompound (30.9 mg, 51% yield). MS (apci) m/z=463.25 (M+H).

Example 520

N-((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide

Step 1: Preparation of4-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. A solution tert-butyl((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 514; 293.5 mg, 0.6133 mmol) in dioxane (2.0 mL) was treatedwith 12 M HCl_((aq)) (100.7 μL, 1.227 mmol). The resulting mixture wasstirred overnight at ambient temperature, then concentrated in vacuo tocleanly afford the title compound (276 mg, 100% yield). MS (apci)m/z=379.2 (M+H).

Step 2: Preparation ofN-((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide.A solution of4-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (112 mg, 0.2481 mmol) in DCM (2 mL) was treated withDIEA (433.4 μL, 2.481 mmol), and then stirred for 5 min at 0° C. Thecold solution was treated dropwise with isovaleryl chloride (60.51 μL,0.4963 mmol). The cooling bath was removed, and the resulting mixturewas stirred for 1 h at ambient temperature. The reaction mixture wasdirectly purified by silica chromatography (using 20-100% EtOAc inHexanes as the gradient eluent) to cleanly provide the title compound(115.7 mg, quantitative yield). MS (apci) m/z=463.2 (M+H).

Example 521

N-((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide

Step 1: Preparation of4-(6-((3S,4R)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. A solution of tert-butyl((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 515; 341.5 mg, 0.7136 mmol) in dioxane (2.0 mL) was treatedwith 12 M HCl_((aq)) (117.2 μL, 1.427 mmol). The resulting mixture wasstirred overnight at ambient temperature, then concentrated in vacuo tocleanly afford the title compound (322 mg, 100% yield). MS (apci)m/z=379.2 (M+H).

Step 2: Preparation ofN-((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide.A solution of4-(6-((3S,4R)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (160.4 mg, 0.3554 mmol) in DCM (2 mL) was treated withDIEA (620.7 μL, 3.554 mmol), and then stirred for 5 min at 0° C. Thecold solution was treated dropwise with isovaleryl chloride (86.65 μL,0.7108 mmol). The cooling bath was removed, and the resulting mixturewas stirred for 1 h at ambient temperature. The reaction mixture wasdirectly purified by silica chromatography (using 30-100% EtOAc inHexanes as the gradient eluent) to cleanly provide the title compound(63.4 mg, 39% yield). MS (apci) m/z=463.2 (M+H).

Example 522

N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-1-(trifluoromethyl)cyclobutane-1-carboxamide

Step 1: Preparation of4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride. A solution of tert-butyl ((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 513; 845.1 mg, 1.766 mmol) in dioxane (3.0 mL) was treated with12 M HCl_((aq)) (290.0 μL, 3.532 mmol). The resulting mixture wasstirred overnight at ambient temperature then concentrated in vacuo tocleanly afford the title compound (797 mg, 100% yield). MS (apci)m/z=379.3 (M+H).

Step 2: Preparation ofN-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-1-(trifluoromethyl)cyclobutane-1-carboxamide.A solution of4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (61.6 mg, 0.136 mmol) and1-(trifluoromethyl)cyclobutane-1-carboxylic acid (45.9 mg, 0.273 mmol)in DCM (1 mL) was treated sequentially with DIEA (119 μL, 0.682 mmol)and HATU (104 mg, 0.273 mmol), then stirred for 1 h at ambienttemperature. The resulting mixture was purified directly by silicachromatography (using 20-100% EtOAc in Hexanes as the gradient eluent)to cleanly provide the title compound (45.5 mg, 63% yield). MS (apci)m/z=529.25 (M+H).

The compounds in Table JJJ were prepared using a similar method to thatdescribed in Step 2 in the synthesis ofN-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-1-(trifluoromethyl)cyclobutane-1-carboxamide(Example 522), replacing 1-(trifluoromethyl)cyclobutane-1-carboxylicacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.The title compounds were isolated following a chromatographicpurification utilizing an appropriate gradient eluent. Where noted (*)an aqueous work up, consisting of dilution of the reaction mixture withDCM and water wash preceded the chromatographic purification.

TABLE JJJ MS (apci) Ex # Structure Chemical Name m/z  523*

3-chloro-N-((3S,4S)-1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4- yl)picolinamide518.15 (M + H) 524

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4-yl)-1-methylcyclobutane- 1-carboxamide 475.3  (M + H) 525

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4- yl)-1-(trifluoromethyl)cyclopropane- 1-carboxamide 515.2  (M + H) 526

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4- yl)-2,3-dimethylbutanamide 477.30 (M + H)

Example 527

trans-3-chloro-N-(()-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methoxypiperidin-4-yl)picolinamide

A solution oftrans-4-(6-(O-4-amino-3-methoxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 511; 26.5 mg, 0.0675 mmol) in DMSO (500 μL) was treatedsequentially with 3-chloropicolinic acid (21.3 mg, 0.135 mmol), DIEA(59.0 μL, 0.338 mmol) and HATU (51.3 mg, 0.135 mmol). The mixture wasstirred 2.5 h at ambient temperature then diluted with DCM, and washedwith water. The organic extracts were purified directly by silicachromatography (using 30-100% EtOAc in Hexanes as the gradient eluent)to cleanly provide the title compound (21.5 mg, 60% yield). MS (apci)m/z=532.2 (M+H).

Example 528

3-chloro-N-((3R,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide

A solution of4-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 520, Step 1; 164 mg, 0.3634 mmol) in DCM (2 mL)was treated sequentially with DIEA (634.6 μL, 3.634 mmol),3-chloropicolinic acid (229.0 mg, 1.453 mmol) and HATU (276.3 mg, 0.7267mmol). The resulting mixture was stirred for 3 h at ambient temperature,and washed with water. The organic extracts were purified directly bysilica chromatography (using 30-100% EtOAc in Hexanes as the gradienteluent) to cleanly provide the title compound (241.1 mg, quantitativeyield). MS (apci) m/z=518.1 (M+H).

Example 529

3-chloro-N-((3S,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide

A solution of4-(6-((3S,4R)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 521, Step 1; 161.6 mg, 0.3580 mmol) in DCM (2mL) was treated sequentially with DIEA (625.3 μL, 3.580 mmol),3-chloropicolinic acid (225.6 mg, 1.432 mmol) and HATU (272.3 mg, 0.7161mmol). The resulting mixture was stirred for 3 h at ambient temperature,and washed with water. The organic extracts were purified directly bysilica chromatography (using 30-100% EtOAc in Hexanes as the gradienteluent) to cleanly provide the title compound (241.1 mg, quantitativeyield). MS (apci) m/z=518.1 (M+H).

Example 530

Trans-isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-methoxypiperidin-4-yl)carbamate

A solution oftrans-4-(6-(4-amino-3-methoxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 511; 50 mg, 0.13 mmol) and DIEA (4.45 μL, 0.0255 mmol) in DCM(500 μL) was treated with isopropyl carbonochloridate (2.34 mg, 0.0191mmol). The resulting mixture was stirred overnight at ambienttemperature, and then directly purified by silica chromatography (using20-80% Hexanes/EtOAc as the gradient eluent) to cleanly provide thetitle compound (6.3 mg, quantitative yield). MS (apci) m/z=479.15 (M+H).

Example 531

Isopropyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate

A solution of4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 518; 50 mg, 0.13 mmol) and DIEA (120 μL, 0.69 mmol) in DCM (2mL) was stirred for 20 min at 0° C. The cold solution was treated withisopropyl chloroformate (33 μL, 0.26 mmol), and the resulting mixturewas stirred for 3 d at ambient temperature. The reaction mixture wasdirectly purified by silica chromatography (using 20-90% EtOAc inHexanes as the gradient eluent) to cleanly provide the title compound(60 mg, 98% yield). MS (apci) m/z=465.2 (M+H).

Example 532

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-ylisopropylcarbamate

A mixture of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 26.4 mg, 0.0935 mmol), 4-methylpiperidin-4-ylIsopropylcarbamate hydrochloride (Intermediate R24; 50 mg, 0.211 mmol)and Cs₂CO_(3(s)) (400 mg, 1.23 mmol) in DMSO (1.0 mL) was stirredovernight at 60° C. The reaction mixture was cooled to ambienttemperature. The reaction mixture was partitioned between DCM and water,then extracted with DCM (3×). The combined organic extracts were driedover Na₂SO_(4(s)), then filtered, and concentrated in vacuo. The cruderesidue was purified first by silica chromatography (using 0-100%Hexanes/EtOAc as the gradient eluent), then by C18 reverse phasechromatography (using 0-70% water/ACN with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt waspartitioned between DCM and saturated NaHCO_(3(aq)), and the biphasicmixture was extracted with DCM (2×). The combined organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto cleanly afford the title compound (2.7 mg, 6% yield). MS (apci)m/z=463.2 (M+H).

Example 533

6-ethoxy-4-(6-(4-((3-fluoro-6-methylpyridin-2-yl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P89, 16.1 mg, 0.0428 mmol), 2,3-difluoro-6-methylpyridine(28.7 mg, 0.222 mmol) and Cs₂CO_(3(s)) (139.3 mg, 0.4277 mmol) in DMSO(1.0 mL) was stirred for 4 d at 60° C. Subsequently, additional2,3-difluoro-6-methylpyridine (28.7 mg, 0.222 mmol) was introduced, andthe reaction mixture was stirred overnight at 100° C. As the reactionhad still not progressed sufficiently, the mixture was cooled to ambienttemperature and DIEA (a few drops) was added. The resulting mixture wasstirred for 7 d at ambient temperature. The reaction mixture waspartitioned between DCM and water, then extracted with DCM (3×). Thecombined organic extracts were dried over Na₂SO_(4(s)), then filtered,and concentrated in vacuo. The crude residue was purified by silicachromatography (using 0-100% Hexanes/EtOAc as the gradient eluent) tocleanly afford the title compound (2.1 mg, 10% yield). MS (apci)m/z=486.2 (M+H).

Example 534

tert-butyl(1-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)cyclopentyl)carbamate

A solution of 1-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylicacid (24 mg, 0.11 mmol) in DMA (445 μL) was treated sequentially withHATU (41 mg, 0.11 mmol),4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P95; 40 mg, 0.089 mmol) and DIEA (78 μL,0.45 mmol). The resulting mixture was stirred for 16 h at ambienttemperature, and then vacuum filtered. The solids were washedsequentially with DMA (3×0.2 mL) and heptane (3×0.5 mL) then dried invacuo. The filtrate was concentrated in vacuo, and purified by C18reverse phase chromatography (using 5-60% ACN in water as the gradienteluent). The solids from the filtration were combined with the purefractions from the chromatography to cleanly afford the title compound(50 mg, 96% yield). MS (apci) m/z=588.3 (M+H); 610.2 (M+Na).

The compounds in Table KKK were prepared using a similar method to thatdescribed in the synthesis of tert-butyl(1-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)cyclopentyl)carbamate(Example 534), replacing1-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid with theappropriate carboxylic acid. Reactions were monitored for completion byLCMS, and reaction durations were adjusted accordingly. Reactions thatproduced suspensions were worked up/purified following a method similarto that used in the synthesis of Example 534 substituting an appropriategradient eluent for the chromatographic purification of the filtrate.For reactions that produced solutions, the reaction mixtures weredirectly subjected to chromatographic purification using an appropriategradient eluent. Either method allowed for the clean isolation of thetitle compounds shown.

TABLE KKK MS (apci) Ex # Structure Chemical Name m/z 535

tert-butyl (S)-(1- ((1-(5-(3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)amino)-1- oxobutan-2-yl)carbamate 562.3 (M + H), 584.3 (M + Na) 536

tert-butyl (1-((1- (5-(3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)carbamoyl)-cyclopropyl)carbamate 560.2 (M + H), 582.3 (M + Na) 537

tert-butyl (1-((1- (5-(3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)carbamoyl)cyclobutyl)-carbamate 574.3 (M + H), 596.2 (M + Na) 538

tert-butyl (S)-(1- ((1-(5-(3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)amino)-1- oxopropan-2-yl)(methyl)carbamate 562.3 (M + H), 584.2 (M + Na) 539

tert-butyl (S)-2- ((1-(5-(3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)carbamoyl)azetidine-1-carboxylate 560.2 (M + H) 540

tert-butyl (4-((1- (5-(3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)carbamoyl)tetrahydro-2H-pyran-4- yl)carbamate 604.3 (M + H), 626.2 (M + Na) 541

N-(1-(5-(3-cyano- 6-ethoxypyrazolo[1, 5-a]pyridin-4- yl)pyridin-2-yl)-4-methylpiperidin-4- yl)-1- (trifluoromethyl)cyclobutane- 1-carboxamide527.2 (M + H), 549.2 (M + Na) 542

N-(1-(5-(3-cyano- 6-ethoxypyrazolo[1, 5-a]pyridin-4- yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-1- hydroxycyclopropane- 1-carboxamide 461.2 (M +H), 483.2 (M + Na) 543

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4- yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-1- methylcyclobutane- 1-carboxamide 473.3 (M + H),495.2 (M + Na)

Example 544

1-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)cyclopentane-1-carboxamideDihydrochloride

A solution of tert-butyl(1-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)cyclopentyl)carbamate(Example 534; 45 mg, 0.077 mmol) in DCM (766 μL) was treated with 5-6 NHCl in iPrOH (306 μL, 1.5 mmol), and stirred overnight at ambienttemperature. The resulting slurry was diluted with MTBE (1 mL) andvacuum filtered. The solids were rinsed with MTBE (3×1 mL), and dried invacuo to cleanly afford the title compound (26 mg, 60% yield). MS (apci)m/z=488.3 (M+H); 510.2 (M+Na).

Example 545

4-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide Dihydrochloride

A solution of tert-butyl(4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)tetrahydro-2H-pyran-4-yl)carbamate(Example 540; 30 mg, 0.050 mmol) in DCM (497 μL) was treated with 5-6 NHCl in iPrOH (199 μL, 0.99 mmol), and stirred overnight at ambienttemperature. The resulting slurry was diluted with MTBE (1 mL) andvacuum filtered. The solids were rinsed with MTBE (3×1 mL), and dried invacuo to cleanly afford the title compound (28 mg, 98% yield). MS (apci)m/z=504.3 (M+H); 526.2 (M+Na).

Example 546

1-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)cyclobutane-1-carboxamideDihydrochloride

A solution of tert-butyl(1-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)cyclobutyl)carbamate(Example 537; 25 mg, 0.044 mmol) in DCM (436 μL) was treated with 5-6 NHCl in iPrOH (174 μL, 0.87 mmol), then stirred for 3 h at ambienttemperature. The resulting mixture was concentrated in vacuo to cleanlyafford the title compound (24 mg, 99% yield). MS (apci) m/z=474.2 (M+H);496.2 (M+Na).

The compounds in Table LLL were prepared using a similar method to thatdescribed in the synthesis of1-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)cyclobutane-1-carboxamidedihydrochloride (Example 546), replacing tert-butyl(1-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)cyclobutyl)carbamate(Example 537) with the appropriate Boc-Protected amino from Table KKK.

TABLE LLL MS (apci) Ex # Structure Chemical Name m/z 547

((S)-2-amino-N-(1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)butanamidedihydrochloride 462.2 (M + H), 484.3 (M + Na) 548

1-amino-N-(1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-methylpiperidin-4- yl)cyclopropane-1-carboxamide dihydrochloride 460.2 (M + H), 482.2 (M + Na) 549

(S)-N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin- 4-yl)-2- (methylamino)propanamide dihydrochloride462.2 (M + H)

Example 550

(S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)azetidine-2-carboxamide

A solution of tert-butyl(S)-2-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamoyl)azetidine-1-carboxylate(Example 539; 40 mg, 0.071 mmol) in DCM (357 μL) was treated with TFA(55 μL, 0.71 mmol). The resulting mixture was stirred overnight atambient temperature then concentrated in vacuo. The residue wasdissolved in MeOH (0.5 mL), and eluted through a basic resin(StratoSpheres Pl-HCO3), rinsing with additional MeOH (3×0.5 mL). Thecombined MeOH filtrates were concentrated in vacuo to cleanly afford thetitle compound as white solid. MS (apci) m/z=460.2 (M+H); 482.2 (M+Na).

Example 551

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-1-(dimethylamino)cyclopentane-1-carboxamide

A solution of1-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)cyclopentane-1-carboxamidedihydrochloride (Example 544; 24 mg, 0.0428 mmol) and formaldehyde (37wt. % in water with 5-15% MeOH stabilizer; 31.9 μL, 0.428 mmol) in DCM(428 μL) was treated with NaBH(AcO)₃ (45.4 mg, 0.214 mmol), and stirredovernight at room temperature. The resulting mixture was directlypurified by C18 reverse phase chromatography (using 5-75% ACN in wateras the gradient eluent) to afford the title compound (21 mg, 94% yield).MS (apci) m/z=516.2 (M+H); 538.2 (M+Na).

The compounds in Table MMM were prepared using a similar method to thatdescribed in the synthesis ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-1-(dimethylamino)cyclopentane-1-carboxamide(Example 551), replacing1-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)cyclopentane-1-carboxamidedihydrochloride (Example 544) with the listed amine. Reactions weremonitored for completion by LCMS, and reaction durations were adjustedaccordingly. Title compounds were isolated following chromatographicpurification using an appropriate gradient eluent.

TABLE MMM Starting MS Amine (apci) Ex # Ex # Structure Chemical Name m/z552 546

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4- yl)pyridin-2-yl)-4-methylpiperidin-4- yl)-1- (dimethylamino)- cyclobutane-1- carboxamide502.2 (M + H), 524.2 (M + Na) 553 550

(S)-N-(1-(5-(3- cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4- methylpiperidin-4- yl)-1- methylazetidine-2-carboxamide 474.2 (M + H), 496.2 (M + Na) 554 545

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4- yl)pyridin-2-yl)-4-methylpiperidin-4- yl)-4- (dimethylamino)- tetrahydro-2H-pyran-4-carboxamide 532.3 (M + H), 554.3 (M + Na)

Example 555

Cyclopropylmethyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P89, 15.9 mg, 0.0422 mmol) and DIEA (14.6 μL, 0.0845 mmol)in DCM (500 μL) was treated with cyclopropylmethyl carbonochloridate(6.82 mg, 0.0507 mmol). The resulting mixture was stirred overnight atambient temperature, and then directly purified by silica chromatography(using 20-80% Hexanes/EtOAc as the gradient eluent) to cleanly providethe title compound (13.4 mg, 66% yield). MS (apci) m/z=475.2 (M+H).

The compounds in Table NNN were prepared using a similar method to thatdescribed in the synthesis of cyclopropylmethyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(Example 555), replacing cyclopropylmethyl carbonochloridate with theappropriate carbonochloridate. Where noted (*) the carbonochloridate isprepared in the reagents section, otherwise commercial reagents wereutilized. Reactions were monitored for completion by LCMS, and reactiondurations were adjusted accordingly. Title compounds were isolatedfollowing chromatographic purification using an appropriate gradienteluent.

TABLE NNN MS (apci) Ex # Structure Chemical Name m/z 556

cyclopentyl (1-(5- (3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)- 4-methylpiperidin- 4-yl)carbamate 489.25 (M + H) 557

ethyl (1-(5-(3- cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)- 4-methylpiperidin- 4-yl)carbamate 449.2 (M + H) 558

isobutyl (1-(5-(3- cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)- 4-methylpiperidin- 4-yl)carbamate 477.2 (M + H)  559*

(S)- tetrahydrofuran- 3-yl (1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)- 4-methylpiperidin- 4-yl)carbamate 491.2(M + H)  560*

cyclobutyl (1-(5- (3-cyano-6- ethoxypyrazolo[1, 5-a]pyridin-4-yl)pyridin-2-yl)- 4-methylpiperidin- 4-yl)carbamate 475.2 (M + H)

Example 561

4-(6-(4-amino-4-((2-morpholinoethoxy)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrilebi s(2,2,2-trifluoroacetate)

A suspension of4-(6-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P56, 40 mg, 0.10 mmol) in DMF (2 mL) was treatedsequentially with NaH (60 wt. % in mineral oil; 41 mg, 1.0 mmol) and4-(2-chloroethyl)morpholine (76 mg, 0.51 mmol). After stirring for 4 hat 50° C., the reaction mixture was cooled to ambient temperature, andquenched with water (2 mL). The quenched mixture was concentrated todryness in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA) to afford the titlecompound (40 mg, 55% yield). MS (apci) m/z=506.3 (M+H).

Example 562

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-morpholinoethoxy)methyl)piperidin-4-yl)-3-methylbutanamide

A solution of4-(6-(4-amino-4-((2-morpholinoethoxy)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile)(Example 561; 25 mg, 0.030 mmol) in DCM (1.0 mL) was treatedsequentially with TEA (8.3 μL, 0.059 mmol) and isovaleryl chloride (4.3μL, 0.036 mmol), then stirred for 30 min at ambient temperature. Thereaction mixture was concentrated in vacuo, and the resulting residuewas purified by silica chromatography (0-7% MeOH in DCM) to cleanlyafford the title compound (1.7 mg, 10% yield). MS (apci) m/z=590.3(M+H).

Example 563

6-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-morpholinoethoxy)methyl)piperidin-4-yl)picolinamide

A suspension of4-(6-(4-amino-4-((2-morpholinoethoxy)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile)(Example 561; 25 mg, 0.049 mmol) in DMF (1 mL) was treated sequentiallywith DIEA (35 μL, 0.20 mmol), 6-chloropicolinic acid (16 mg, 0.099 mmol)and HATU (38 mg, 0.099 mmol). The resulting mixture was stirred for 15 hat ambient temperature. The mixture was diluted with EtOAc (20 mL), andwashed sequentially with saturated NaHCO_(3(aq)), and water. Thecombined organic extracts were concentrated in vacuo. The organicextracts were purified directly by silica chromatography (0-7% MeOH inDCM) to cleanly afford the title compound (21 mg, 66% yield). MS (apci)m/z=645.2 (M+H).

Example 564

3-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-morpholinoethoxy)methyl)piperidin-4-yl)picolinamide

The title compound (12 mg, 52% yield) was prepared and worked up using asimilar procedure to that described for6-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-morpholinoethoxy)methyl)piperidin-4-yl)picolinamide(Example 563), replacing 6-chloropicolinic acid with 3-chloropicolinicacid. MS (apci) m/z=645.2 (M+H).

Example 565

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-morpholinoethoxy)methyl)piperidin-4-yl)-4-methylbenzenesulfonamide

Under an inert atmosphere (N_(2(g))), a suspension of6-ethoxy-4-(6-(1-tosyl-1,6-diazaspiro[2.5]octan-6-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate R51; 40 mg, 0.076 mmol), 2-morpholinoethan-1-ol (30 mg,0.23 mmol) and 18-Crown-6 (40 mg, 0.15 mmol) in DMA (1.5 mL) was cooledto −10° C., then treated with a 1 M solution of KOtBu in THF (150 μL,1.0 mmol). The reaction mixture was stirred for 30 min at −10 OC, thenallowed to stir for an additional 1 h at temperatures between −10° C.-0°C. The reaction mixture was quenched with saturated NH₄Cl_((aq)), anddiluted with water (2 mL). The resulting suspension was filtered. Thesolids were rinsed with water (20 mL), then dried in vacuo to afford thetitle compound (38 mg, 76% yield). MS (apci) m/z=660.3 (M+H).

Example 566

N-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)-4-methylbenzenesulfonamide

A solution of 6-ethoxy-4-(6-(1-tosyl-1,6-diazaspiro[2.5]octan-6-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate R51; 26 mg, 0.049 mmol) in dioxane (2 mL) and 2 MH₂SO_(4(aq)) (1 mL, 2.00 mmol) was stirred for 15 h at ambienttemperature. The reaction mixture was quenched with 2 M K₂CO_(3(aq)) (5mL) and extracted with EtOAc. The organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered, concentrated in vacuo. The residue wastriturated with MTBE, and filtered. The solids collected were purifiedby silica chromatography (using 0-70% EtOAc in Hexanes as the gradienteluent) to cleanly afford the title compound (17 mg, 63% yield). MS(apci) m/z=547.2 (M+H).

Example 567

N-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)benzenesulfonamide

A solution of6-ethoxy-4-(6-(1-(phenylsulfonyl)-1,6-diazaspiro[2.5]octan-6-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate R52; 10.5 mg, 0.0204 mmol) in dioxane (2 mL) and 2 MH₂SO_(4(aq)) (0.5 mL, 1.00 mmol) was stirred for 1 h at ambienttemperature. The reaction mixture was quenched with 2 M Na₂CO_(3(aq)) (5mL), and diluted with water. The resulting suspension was extracted withDCM. The organic extracts were concentrated in vacuo, and the residuewas purified by silica chromatography (using 0-100% EtOAc in Hexanes asthe gradient eluent) to cleanly afford the title compound (1.8 mg, 17%yield). MS (apci) m/z=533.2 (M+H).

Example 568

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-2-(1-methoxycyclopropyl)acetamideStep 1. Preparation of ethyl 2-cyclopropylideneacetate

A solution of ((1-ethoxycyclopropyl)oxy)trimethylsilane (2.30 mL, 11.5mmol) in toluene (29 mL) was treated with(carboethoxymethylene)triphenylphosphorane (4.20 g, 12.0 mmol) andbenzoic acid (1.54 g, 12.6 mmol), then stirred at 90° C. for 2 hrs.After cooled to RT, the reaction mixture was directly purified by silicachromatography (0 to 50% EtOAc in hexanes) to yield the title product(1.1 g, 75%).

Step 2. Preparation of 2-(1-methoxycyclopropyl)acetic Acid

To a solution of ethyl 2-cyclopropylideneacetate (0.50 g, 3.96 mmol) inMeOH (10 mL) was added trimethylphosphine (0.0205 mL, 0.198 mmol). Thereaction was sealed and heated at 45° C. for 3 d. After removal of mostsolvent under vacuum, the residue was taken up in MeOH and treated withNaOH (2 N, aq; 3.96 mL) at RT for overnight. The reaction mixture wasconcentrated first, then diluted with water (5 mL) and washed withwashed with EtOAc (2×). After phase-separation, the aqueous layer wasacidified to pH˜2 and then extracted with EtOAc (2×). The combinedorganics were dried (Na₂SO₄), filtered and concentrated to yield thetitle product (0.2 g, 39%).

Step 3. Preparation ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-2-(1-methoxycyclopropyl)acetamide.A mixture of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 32.2 mg, 0.0768 mmol), 2-(1-methoxycyclopropyl)aceticacid (10 mg, 0.077 mmol) and HATU (73.0 mg, 0.192 mmol) in DCM (154 μL)was treated with DIEA (134 μL, 0.768 mmol), then stirred overnight atambient temperature. The resulting mixture was concentrated in vacuo,and the residue was purified by C18 reverse phase chromatography (using5-95% water:ACN with 0.1% TFA as the gradient eluent). Fractionscontaining the desired compound were combined, diluted with 4:1DCM:iPrOH, and extracted sequentially with saturated NaHCO_(3(aq)) andbrine. The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (26 mg,64% yield). MS (apci) m/z=532.3 (M+H).

Example 569

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-2,3-dimethylbutanamide

The title compound (21 mg, 43% yield) was prepared and worked up using asimilar procedure to that described forN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-2-(1-methoxycyclopropyl)acetamide(Example 568), replacing 2-(1-methoxycyclopropyl)acetic acid with2,3-dimethylbutanoic acid. MS (apci) m/z=518.3 (M+H).

Example 570

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-fluoropicolinamide

A solution of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 50 mg, 0.119 mmol) in DMSO (795 μL) was treatedsequentially with 3-fluoropicolinic acid (0.0252 g, 0.179 mmol), DIEA(93.4 μL, 0.536 mmol) and HATU (90.6 mg, 0.238 mmol). The resultingmixture was stirred overnight at ambient temperature, and thenpartitioned between EtOAc and water. The organic extracts were washedwith brine, dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The crude residue was purified by C18 reversephase chromatography (using 5-95% water:ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was dissolved in DCM, and extracted sequentially with saturatedNaHCO_(3(aq)) and brine. The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (40.1 mg, 62% yield). MS (apci) m/z=543.3 (M+H).

Example 571

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-(trifluoromethyl)picolinamide

The title compound (24 mg, 34% yield) was prepared, worked up andpurified using a similar procedure to that described forN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-fluoropicolinamide(Example 570), replacing 3-fluoropicolinic acid with3-(trifluoromethyl)picolinic acid. MS (apci) m/z=593.3 (M+H).

Example 572

Isobutyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate

A solution of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 30 mg, 0.072 mmol) and TEA (20 μL, 0.14 mmol) in DCM(715 μL) was treated with isobutyl chloroformate (9.4 μL, 0.072 mmol),and the resulting mixture was stirred for 6 d at ambient temperature.The reaction mixture was concentrated in vacuo, and the residue waspurified by C18 reverse phase chromatography (using 5-95% water:ACN with0.1% TFA as the gradient eluent). Fractions containing the desiredproduct were combined, diluted with 4:1 DCM:iPrOH, then extractedsequentially with saturated NaHCO_(3(aq)) and brine. The organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (30 mg, 81% yield).MS (apci) m/z=520.3 (M+H).

Example 573

Neopentyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate

The title compound (18 mg, 44% yield) was prepared, worked up andpurified using a similar procedure to that described for isobutyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate(Example 572), replacing isobutyl chloroformate with neopentylchloroformate. MS (apci) m/z=534.4 (M+H).

Example 574

Cyclopropylmethyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate

The title compound (21 mg, 57% yield) was prepared, worked up andpurified using a similar procedure to that described for isobutyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate(Example 572), replacing isobutyl chloroformate (1 equivalent) withcyclopropylmethyl chloroformate (1.2 equivalents). MS (apci) m/z=518.3(M+H).

Example 575

1-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-isobutylurea

A solution of4-(6-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P72, 30 mg, 0.072 mmol) and DIEA (125 μL, 0.715 mmol) inDMA (1.4 mL) was treated with 4-nitrophenyl chloroformate (17.3 mg,0.0858 mmol). The resulting mixture was stirred for 1 h at ambienttemperature, before adding isobutylamine (35.5 μL, 0.358 mmol). Theresulting mixture was stirred overnight at 80° C. After cooling toambient temperature, the reaction mixture was concentrated in vacuo, andthe residue was purified by C18 reverse phase chromatography (using5-95% water:ACN with 0.1% TFA as the gradient eluent). Fractionscontaining the desired product were combined, diluted with 4:1DCM:iPrOH, then extracted sequentially with saturated NaHCO_(3(aq)) (1×)and brine (2×). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (35 mg, 94% yield). MS (apci) m/z=519.3 (M+H).

Example 576

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)pyrrolidine-1-carboxamide

The title compound (25 mg, 68% yield) was prepared using a similarprocedure to that described for1-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-isobutylurea(Example 575), replacing isobutylamine (5 equivalents) with pyrrolidine(1 equivalent). The cooled reaction mixture was diluted with water thenextracted with EtOAc. The EtOAc extracts were washed sequentially withwater and brine, then dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo, prior to employing similar purification/freebasing steps as those used in Example 575. MS (apci) m/z=517.3 (M+H).

Example 577

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)piperidine-1-carboxamide

The title compound (25 mg, 68% yield) was prepared using a similarprocedure to that described for1-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-isobutylurea(Example 575), replacing isobutylamine (5 equivalents) with piperidine(1 equivalent). For the work up, the cooled reaction mixture was dilutedwith water then extracted with EtOAc. The EtOAc extracts were washedsequentially with water and brine then dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo, prior to employingsimilar purification/free basing steps as those used in Example 575. MS(apci) m/z=531.3 (M+H).

Example 578

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((dimethylamino)methyl)-N-isobutylpiperidine-4-carboxamide

A solution of dimethylamine hydrochloride (41.7 mg, 0.511 mmol) in DCM(1.0 ml) was treated with triethylamine (69.3 μL, 0.511 mmol) andstirred for 5 min at ambient temperature before introducing1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 48.5 mg, 0.102 mmol). The resulting mixture wastreated with NaBH(AcO)₃ (108 mg, 0.511 mmol), stirred overnight at roomtemperature, and then concentrated in vacuo. The crude residue waspurified by C18 reverse phase chromatography (using 5-95% water-ACN with0.1% TFA as the gradient eluent). Fractions containing the desiredproduct were diluted with 4:1 DCM:iPrOH, and extracted with saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to cleanly afford thetitle compound (23.1 mg, 45% yield). MS (apci) m/z=504.3 (M+H).

Example 579

4-(azetidin-1-ylmethyl)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 58.6 mg, 0.123 mmol) in DCM (1.2 mL) was treatedsequentially with azetidine (41.6 μL, 0.617 mmol) and NaBH(AcO)₃ (131mg, 0.617 mmol), and stirred for 16 h at ambient temperature. Thereaction mixture was concentrated in vacuo. The crude residue waspurified directly by C18 reverse phase chromatography (using 5-95%water:ACN with 0.1% TFA as the gradient eluent). Fractions containingthe desired product were partitioned between 4:1 DCM:iPrOH and saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (42.8 mg, 57% yield). MS (apci) m/z=516.4 (M+H).

Example 580

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyrrolidin-1-ylmethyl)piperidin-4-yl)-3-methylbutanamide

A solution of4-(6-(4-amino-4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P97; 30 mg, 0.065 mmol) and TEA (19 μL, 0.13 mmol) in DCM(673 μL) was treated with isovaleryl chloride (8.2 μL, 0.067 mmol), andthen stirred overnight at ambient temperature. The reaction mixture waspurified directly by C18 reverse phase chromatography (using 5-95%water:ACN with 0.1% TFA as the gradient eluent). Fractions containingthe desired product were combined, diluted with 4:1 DCM:iPrOH, thenextracted sequentially with saturated NaHCO_(3(aq)) (1×) and brine (2×).The organic extracts were dried over anhydrous Na₂SO_(4(s)), filtered,and concentrated in vacuo to afford the title compound (23 mg, 64%yield). MS (apci) m/z=530.4 (M+H).

Example 581

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-(pyrrolidin-1-ylmethyl)piperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 54.6 mg, 0.115 mmol) in DCM (1.2 mL) was treatedsequentially with pyrrolidine (48.0 μL, 0.575 mmol) and NaBH(AcO)₃ (122mg, 0.575 mmol), and stirred for 16 h at ambient temperature. Thereaction mixture was concentrated in vacuo. The crude residue waspurified directly by C18 reverse phase chromatography (using 5-95%water:ACN with 0.1% TFA as the gradient eluent). Fractions containingthe desired product were partitioned between 4:1 DCM:iPrOH, andsaturated NaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (44.4 mg, 73% yield). MS (apci) m/z=530.2 (M+H).

Example 582

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)-3-methylbutanamide

A solution of4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P73, 30 mg, 0.065 mmol) and TEA (18 μL, 0.13 mmol) in DCM(650 μL) was treated with isovaleryl chloride (7.9 μL, 0.065 mmol), andthen stirred overnight at ambient temperature. The mixture was treatedwith additional isovaleryl chloride (7.9 μL, 0.065 mmol), and stirredfor an additional 3 h. The resulting mixture was diluted with 4:1DCM:iPrOH, and then extracted with saturated NaHCO_(3(aq)), water (1×)and brine (2×). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to cleanly afford thetitle compound (35 mg, 99% yield). MS (apci) m/z=546.3 (M+H).

Example 583

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)propionamide

A solution of4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P73, 40 mg, 0.087 mmol) and TEA (24 μL, 0.17 mmol) in DCM(867 μL) was treated with propionyl chloride (8.0 mg, 0.087 mmol), andthen stirred overnight at ambient temperature. The mixture wasconcentrated in vacuo and the residue was purified by C18 reverse phasechromatography (5-95% water:ACN with 0.1% TFA). Fractions containing thedesired product were combined, diluted with 4:1 DCM:iPrOH, and thenextracted with saturated NaHCO_(3(aq)), water (1×) and brine (2×). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo to cleanly afford the title compound (31 mg, 69%yield). MS (apci) m/z=518.3 (M+H).

Example 584

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)butyramide

The title compound (29 mg, 63% yield) was prepared, worked up andpurified using a similar procedure to that described forN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)propionamide(Example 583), replacing propionyl chloride with butyryl chloride. MS(apci) m/z=532.4 (M+H).

Example 585

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)-3,3,3-trifluoropropanamide

The title compound (29 mg, 47% yield) was prepared, worked up andpurified using a similar procedure to that described forN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)propionamide(Example 583), replacing propionyl chloride with3,3,3-trifluoropropionyl chloride. MS (apci) m/z=572.3 (M+H).

Example 586

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)-4,4,4-trifluoro-3-methylbutanamide

A mixture of4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P73, 30 mg, 0.065 mmol), 3-trifluoromethylbutyric acid (10mg, 0.065 mmol) and HATU (62 mg, 0.16 mmol) in DCM (130 L) was treatedwith DIEA (114 μL, 0.65 mmol), then stirred for 3 d at ambienttemperature. The resulting mixture was concentrated in vacuo, and theresidue was purified by C18 reverse phase chromatography (using 5-95%water:ACN with 0.1% TFA as the gradient eluent). Fractions containingthe desired compound were combined, diluted with 4:1 DCM:iPrOH, andextracted sequentially with saturated NaHCO_(3(aq)) and brine. Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (31 mg, 80% yield).MS (apci) m/z=600.3 (M+H).

The compounds in Table 000 were prepared using a similar method to thatdescribed in the synthesis ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)-4,4,4-trifluoro-3-methylbutanamide(Example 586), replacing 3-trifluoromethylbutyric acid with theappropriate carboxylic acid. Where noted (*) the carboxylic acid isprepared in the reagents section, otherwise commercial reagents wereutilized. Reactions were monitored for completion by LCMS, and reactiondurations were adjusted accordingly. Title compounds were isolatedfollowing chromatographic purification using an appropriate gradienteluent. When chromatographic conditions resulted in the isolation of theTFA salt of the title compound, chromatography was followed by a basicwork up as in Example 586.

TABLE OOO MS (apci) Ex # Structure Chemical Name m/z 587

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4- yl)pyridin-2-yl)-4-(morpholinomethyl)- piperidin-4-yl)-2,3- dimethylbutanamide 560.3 (M +H) 588

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4- yl)pyridin-2-yl)-4-(morpholinomethyl)- piperidin-4-yl)-3- hydroxy-3- methylbutanamide 562.3(M + H) 589

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4- yl)pyridin-2-yl)-4-(morpholinomethyl)- piperidin-4-yl)-3- methoxy-3- methylbutanamide 576.4(M + H) 590

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4- yl)pyridin-2-yl)-4-(morpholinomethyl)- piperidin-4-yl)-1- methoxycyclopropane-1-carboxamide 560.3 (M + H)

Example 591

(R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)-3-hydroxybutanamide

A mixture of4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P73, 30 mg, 0.065 mmol), (R)-3-hydroxybutyric acid (6.8mg, 0.065 mmol) and HATU (25 mg, 0.065 mmol) in DCM (650 μL) was treatedwith DIEA (11 μL, 0.065 mmol), then stirred for 3 d at ambienttemperature. The resulting mixture was concentrated in vacuo, and theresidue was purified by C18 reverse phase chromatography (using 5-95%water:ACN with 0.1% TFA as the gradient eluent). Fractions containingthe desired compound were combined, diluted with 4:1 DCM:iPrOH, andextracted sequentially with saturated NaHCO_(3(aq)) and brine. Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (17 mg, 48% yield).MS (apci) m/z=548.3 (M+H).

Example 592

Ethyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)carbamate

A solution of4-(6-(4-amino-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P73, 25 mg, 0.054 mmol) and DIEA (18.9 μL, 0.108 mmol) inDCM (500 μL) was treated with ethyl carbonochloridate (7.05 mg, 0.0650mmol). The resulting mixture was stirred overnight at ambienttemperature, and then directly purified by silica chromatography (using40-100% Hexanes/EtOAc as the gradient eluent) to cleanly provide thetitle compound (20.5 mg, 70% yield). MS (apci) m/z=534.2 (M+H).

Example 593

Isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)carbamate

The title compound (22 mg, 64% yield) was prepared, worked up andpurified using a similar procedure to that described for ethyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(morpholinomethyl)piperidin-4-yl)carbamate(Example 592), replacing ethyl carbonochloridate with isopropylcarbonochloridate. MS (apci) m/z=548.2 (M+H).

Example 594

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-2,3-dimethylbutanamide

A mixture of4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P74, 40 mg, 0.082 mmol), 2,3-dimethylbutanoic acid (9.5mg, 0.082 mmol) and HATU (78 mg, 0.20 mmol) in DCM (164 μL) was treatedwith DIEA (143 μL, 0.820 mmol). The resulting mixture was stirredovernight at ambient temperature, and then concentrated in vacuo. Thecrude residue was purified by C18 reverse phase chromatography (5-95%ACN:water with 0.1% TFA). Fractions containing the desired product werecombined, diluted with 4:1 DCM:iPrOH, then sequentially extracted withsaturated NaHCO_(3(aq)), water and brine. The organic extracts weredried over anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuoto cleanly afford the title compound (18 mg, 37% yield). MS (apci)m/z=587.4 (M+H).

Example 595

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)isobutyramide

A solution of4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P98; 9.5 mg, 0.0169 mmol), isobutyric acid(1.86 mg, 0.0211 mmol) and DIEA (14.8 μL, 0.0846 mmol) in DMF (169 μL)was treated with HATU (8.04 mg, 0.0211 mmol). The resulting mixture wasstirred for 5 min at ambient temperature, and then purified by silicachromatography (using 0-10% [MeOH with 1% NH₄OH] in EtOAc as thegradient eluent). The purified residue was triturated with MTBE thenconcentrated in vacuo to cleanly afford the title compound (9 mg, 95%yield). MS (apci) m/z=559.3 (M+H).

Example 596

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-2-(trifluoromethyl)benzamide

The title compound can be prepared in a similar fashion as described forN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)isobutyramide(Example 595), replacing isobutyric acid with 2-(trifluoromethyl)benzoicacid.

Example 597

3-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-5-fluoropicolinamide

A solution of4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P74, 23.5 mg, 0.0481 mmol) in DMSO (481 μL) was treatedwith DIEA (42.0 μL, 0.240 mmol), 3-chloro-5-fluoropicolinic acid (16.9mg, 0.0962 mmol) and HATU (36.6 mg, 0.0962 mmol). The resulting mixturewas stirred overnight at ambient temperature, and then purified directlyby silica chromatography (using 0-10% [MeOH with 1% NH₄OH] in DCM as thegradient eluent) to cleanly afford the title compound (20.6 mg, 66%yield). MS (apci) m/z=646.3 (M+H).

Example 598

5-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-2-methylnicotinamide

The title compound (17.2 mg, 56% yield) was prepared, worked up andpurified using a similar procedure to that described for3-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-5-fluoropicolinamide(Example 597), replacing 3-chloro-5-fluoropicolinic acid (2 equivalents)with 5-chloro-2-methyl-3-pyridinecarboxylic acid (1 equivalent). MS(apci) m/z=642.4 (M+H).

Example 599

3-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)picolinamide

A solution of4-(6-(4-amino-4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P98; 31.9 mg, 0.0568 mmol) in DMF (169 μL)was treated with DIEA (9.2 μL, 0.0568 mmol), 3-chloropicolinic acid(26.9 mg, 0.170 mmol) and HATU (43.2 mg, 0.114 mmol). The resultingmixture was stirred for 30 min at ambient temperature, and then purifieddirectly by silica chromatography (using 10-25% [MeOH with 1% NH₄OH] inDCM as the gradient eluent) to cleanly afford the title compound (23.4mg, 66% yield). MS (apci) m/z=628.3 (M+H).

Example 600

Ethyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

The title compound (13.7 mg, 51% yield) was prepared, worked up andpurified using a similar procedure to that described for methyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate(Example 392), with the following exceptions, methyl chloroformate wasreplaced with ethyl chloroformate, and the reaction was allowed to stironly 1 h before filtering. MS (apci) m/z=561.3 (M+H).

Example 601

Isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

The title compound (8.5 mg, 30% yield) was prepared, worked up andpurified using a similar procedure to that described for methyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate(Example 392), with the following exceptions, methyl chloroformate wasreplaced with isopropyl chloroformate, and the reaction was allowed tostir overnight before filtering. MS (apci) m/z=574.4 (M+H).

Example 602

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 51.8 mg, 0.109 mmol) in DCM (1.0 mL) was treatedsequentially with 1-ethylpiperazine (69.3 μL, 0.546 mmol) and NaBH(AcO)₃(116 mg, 0.546 mmol), and stirred for 16 h at ambient temperature. Thereaction mixture was concentrated in vacuo. The crude residue waspurified directly by C18 reverse phase chromatography (using 5-95%water:ACN with 0.1% TFA as the gradient eluent). Fractions containingthe desired product were partitioned between 4:1 DCM:iPrOH and saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to afford the titlecompound (32.3 mg, 52% yield). MS (apci) m/z=573.4 (M+H).

Example 603

(S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide

A solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-3-methylbutanamide(Intermediate P102; 500 mg, 1.189 mmol) in DCM (5 mL) was treated with(S)-1,2-dimethylpiperazine (Intermediate R28; 42.6 mg, 0.373 mmol), andstirred for 2 h at ambient temperature. The resulting mixture wastreated with NaBH(AcO)₃ (63.2 mg, 0.298 mmol), and stirred overnight atambient temperature. The reaction mixture was diluted with DCM andextracted with saturated NaHCO_(3(aq)). The organic extracts werepurified directly by silica chromatography (using 0-20% [MeOH with 1%NH₄OH] in DCM as the gradient eluent) to cleanly afford the titlecompound (5.4 mg, 12% yield). MS (apci) m/z=573.3 (M+H).

Example 604

(S)-3-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-4-yl)picolinamide

A solution of(S)-4-(6-(4-amino-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P155; 37.0 mg, 0.0757 mmol) in DCM (2 mL) was treated withDIEA (132 μL, 0.757 mmol), 3-chloropicolinic acid (35.8 mg, 0.227 mmol)and HATU (57.6 mg, 0.151 mmol). The resulting mixture was stirredovernight at ambient temperature, and then purified directly by silicachromatography (using 0-20% [MeOH with 1% NH₄OH] in DCM as the gradienteluent). Fractions containing the desired product were concentrated, andthe resultant residue was taken up with saturated NaHCO_(3(aq)) andextracted into EtOAc. The organic extracts were dried over Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (14.6mg, 29% yield). MS (apci) m/z=628.2 (M+H).

Example 605

tert-butyl(S)-4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((isopropoxycarbonyl)amino)piperidin-4-yl)methyl)-2-methylpiperazine-1-carboxylate

A solution of isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(Intermediate P105; 47.8 mg, 0.100 mmol) in DCE (3 mL) was treated withtert-butyl (S)-2-methylpiperazine-1-carboxylate (100 mg, 0.502 mmol),and stirred for 45 min at ambient temperature. The resulting mixture wastreated with NaBH(AcO)₃ (128 mg, 0.602 mmol), and stirred for 1.5 h atambient temperature. The reaction mixture was diluted with DCM, andextracted with water. The organic extracts were purified directly bysilica chromatography (first using 0-25% MeOH in DCM as the gradienteluent, then using 0-40% [MeOH with 1% NH₄OH] in EtOAc) to afford thetitle compound (44.5 mg, 63% yield). MS (apci) m/z=661.3 (M+H).

Example 606

Isopropyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3-methylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

A solution of tert-butyl(S)-4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((isopropoxycarbonyl)amino)piperidin-4-yl)methyl)-2-methylpiperazine-1-carboxylate(Example 605; 23.1 mg, 0.0350 mmol) in dioxane (500 μL) was treated with12 M HCl_((aq)) (5.74 μL, 0.0699 mmol). The resulting mixture wasstirred for 1 h at ambient temperature, then concentrated in vacuo. Thecrude residue was dissolved in 4:1 DCM:iPrOH, then extracted withsaturated NaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to cleanly afford thetitle compound (21.5 mg, quantitative yield). MS (apci) m/z=561.3 (M+H).

Example 607

Isopropyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

A solution of isopropyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3-methylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate(Example 606; 12.5 mg, 0.02229 mmol) in DCE (1.0 mL) was treated withformaldehyde (37 wt. % in water with 5-15% MeOH stabilizer; 9.046 mg,0.1115 mmol), and stirred for 45 min at ambient temperature. Theresulting mixture was treated with NaBH(AcO)₃ (28.35 mg, 0.1338 mmol),stirred for 2 h at ambient temperature, and then concentrated in vacuo.The crude residue was suspended in 4:1 DCM:iPrOH and then filtered. Thefiltrate was concentrated in vacuo to cleanly provide the title compound(8.7 mg, 64% yield). MS (apci) m/z=575.3 (M+H).

Example 608

Phenyl(S)-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

A solution of(S)-4-(6-(4-amino-4-((3,4-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P155; 33.1 mg, 0.0677 mmol) in DCM (2 mL) was treated withDIEA (47.3 μL, 0.271 mmol) and phenyl carbonochloridate (12.8 μL, 0.102mmol). The resulting mixture was stirred overnight at ambienttemperature, then diluted with DCM. The DCM solution was extracted withsaturated NaHCO_(3(aq)). The organic extracts were purified by silicachromatography (using 0-20% [MeOH with 1% NH₄OH] in DCM as the gradienteluent) to cleanly provide the title compound (1.4 mg, 3% yield). MS(apci) m/z=609.3 (M+H).

Example 609

Tert-butyl4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((isopropoxycarbonyl)amino)piperidin-4-yl)methyl)piperazine-1-carboxylate

A solution of isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(Intermediate P105; 38.9 mg, 0.0816 mmol) in DCE (1.5 mL) was treatedwith tert-butyl piperazine-1-carboxylate (76.0 mg, 0.408 mmol), andstirred for 45 min at ambient temperature. The resulting mixture wastreated with NaBH(AcO)₃ (104 mg, 0.490 mmol), and stirred for 1.5 h atambient temperature. The reaction mixture was diluted with DCM andextracted with water. The organic extracts were purified directly bysilica chromatography (using 0-100% EtOAc in hexanes as the gradienteluent) to cleanly afford the title compound (19.7 mg, 37% yield). MS(apci) m/z=647.3 (M+H).

Example 610

Isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)carbamate

A solution of tert-butyl4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((isopropoxycarbonyl)amino)piperidin-4-yl)methyl)piperazine-1-carboxylate(Example 609; 14.5 mg, 0.0224 mmol) in dioxane (500 μL) was treated with12 M HCl_((aq)) (3.68 μL, 0.0448 mmol). The resulting mixture wasstirred for 1 h at ambient temperature then concentrated in vacuo. Thecrude residue was dissolved in 4:1 DCM:iPrOH, then extracted withsaturated NaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered, and concentrated in vacuo to cleanly afford thetitle compound (8.5 mg, 69% yield). MS (apci) m/z=547.25 (M+H).

Example 611

Isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-methylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

A solution of isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)carbamate(Example 610; 5.7 mg, 0.010 mmol) in DCE (1.0 mL) was treated withformaldehyde (37 wt. % in water with 5-15% MeOH stabilizer; 4.231 mg,0.05213 mmol), and stirred for 45 min at ambient temperature. Theresulting mixture was treated with NaBH(AcO)₃ (13.26 mg, 0.06256 mmol),stirred for 2 h at ambient temperature, and then concentrated in vacuo.The crude residue was dissolved in DCM, then extracted sequentially withwater and saturated NaHCO_(3(aq)). After back extracting the aqueousextracts with DCM, the organic extracts were combined, dried overanhydrous Na₂SO_(4(s)), and filtered. The filtrate was directly purifiedsilica chromatography (using 0-30% [MeOH with 1% NH₄OH] in DCM as thegradient eluent) to cleanly provide the title compound (2.1 mg, 36%yield). MS (apci) m/z=561.3 (M+H).

Example 612

Isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(2-((1-methylpiperidin-4-yl)amino)ethyl)piperidin-4-yl)carbamate

A solution of isopropyl(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate(Intermediate P105; 35.5 mg, 0.0745 mmol) in DCE (1.0 mL) was treatedwith 1-methylpiperidin-4-amine (42.5 mg, 0.372 mmol), and stirred for 45min at ambient temperature. The resulting mixture was treated withNaBH(AcO)₃ (94.7 mg, 0.447 mmol), and stirred overnight at ambienttemperature. The reaction mixture was diluted with DCM, and extractedsequentially with water and saturated NaHCO_(3(aq)). After backextracting the aqueous extracts with DCM, the organic extracts werecombined, dried over anhydrous Na₂SO_(4(s)), and filtered. The filtratewas purified directly by silica chromatography (using 0-50% [MeOH with1% NH₄OH] in DCM as the gradient eluent) to cleanly afford the titlecompound (2.3 mg, 5% yield). MS (apci) m/z=575.3 (M+H).

Example 613

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

A solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P70, 33.6 mg, 0.0638 mmol) and1-(2-methoxyethyl)piperazine (28.5 μL, 0.191 mmol) in DCM (319 μL) wasstirred for 30 min at ambient temperature. The resulting mixture wastreated with NaBH(AcO)₃ (20.3 mg, 0.0957 mmol), and stirred overnight atroom temperature. The resulting mixture was directly purified by silicachromatography (using 0-10% [9:1 DCM:MeOH with 1% NH₄OH] in DCM as thegradient eluent) to afford the title compound (30.3 mg, 73% yield). MS(apci) m/z=655.4 (M+H).

Example 614

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

A solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((2-hydroxy-2-methylpropyl)amino)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 381; 30.6 mg, 0.0510 mmol) and formaldehyde (37 wt. % in waterwith 5-15% MeOH stabilizer; 19.2 μL, 0.255 mmol) in DCE (255 μL) wasstirred for 30 min at ambient temperature. The resulting mixture wastreated with NaBH(AcO)₃ (108 mg, 0.510 mmol), and stirred overnight atroom temperature. The resulting mixture was directly purified by silicachromatography (using 0-10% [9:1 DCM:MeOH with 1% NH₄OH] in DCM as thegradient eluent) to afford the title compound (26.5 mg, 85% yield). MS(apci) m/z=614.4 (M+H).

Example 615

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3-hydroxy-3-methylazetidin-1-yl)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

A solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Intermediate P70, 44.3 mg, 0.0841 mmol), 3-hydroxy-3-methylazetidinehydrochloride (31.2 mg, 0.252 mmol) and DIEA (44.1 μL, 0.252 mmol) inDCM (421 μL) was stirred for 30 min at ambient temperature. Theresulting mixture was treated with NaBH(AcO)₃ (26.7 mg, 0.126 mmol), andstirred overnight at room temperature. The resulting mixture wasdirectly purified by silica chromatography (using 0-10% [9:1 DCM:MeOHwith 1% NH₄OH] in DCM as the gradient eluent) to afford the titlecompound (42.2 mg, 84% yield). MS (apci) m/z=598.3 (M+H).

Example 616

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((2,2-difluoroethyl)(methyl)amino)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

The title compound (17.5 mg, 35% yield) was prepared, worked up andpurified using a similar procedure to that described forN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3-hydroxy-3-methylazetidin-1-yl)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 615), replacing 3-hydroxy-3-methylazetidine hydrochloride with2,2-difluoro-N-methylethanamine hydrochloride. MS (apci) m/z=606.3(M+H).

Example 617

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide

The title compound (45.4 mg, 84% yield) was prepared, worked up andpurified using a similar procedure to that described forN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3-hydroxy-3-methylazetidin-1-yl)methyl)piperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 615), replacing 3-hydroxy-3-methylazetidine hydrochloride with3,3-difluoropyrrolidine hydrochloride. MS (apci) m/z=618.3 (M+H).

Example 618

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-2-(1-methyl-1H-imidazol-2-yl)acetamide

A solution of2-(1-methyl-1H-imidazol-2-yl)-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)acetamidebis(2,2,2-trifluoroacetate) (Intermediate R33; 92.9 mg, 0.172 mmol),6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 44 mg, 0.156 mmol) and K₂CO_(3(s)) (108 mg, 0.779mmol) in DMSO (1039 μL) was stirred overnight at 90° C. After cooling toambient temperature, the mixture was filtered, and the filtrate waspurified directly by C18 reverse phase chromatography (using 5-95%ACN/water with 0.1% TFA as the gradient eluent) to afford the titlecompound as the TFA salt. The TFA salt was suspended in MeOH (5 mL),eluted through a basic resin (Stratospheres Pl-HCO3) to cleanly affordthe title compound (34.9 mg, 39% yield). MS (apci) m/z=576.3 (M+H).

The compounds in Table PPP were prepared, worked up, purified and freebased using a similar method to that described in the synthesis ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-2-(1-methyl-1H-imidazol-2-yl)acetamide(Example 618), replacing2-(1-methyl-1H-imidazol-2-yl)-N-(4-(pyridin-2-ylmethyl)piperidin-4-yl)acetamidebis(2,2,2-trifluoroacetate) (Intermediate R33) with the appropriateamine (1.0-1.5 equivalents). Reactions were monitored for completion byLCMS, and reaction durations were adjusted accordingly.

TABLE PPP MS (apci) Ex # Structure Chemical Name m/z 619

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2- ylmethyl)piperidin-4-yl)- 2-(dimethylamino)- acetamide539.3 (M + H) 620

(R)-N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2- ylmethyl)piperidin-4-yl)- 1-methylpyrrolidine-2-carboxamide 565.3 (M + H) 621

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2- ylmethyl)piperidin-4-yl)- 2-(piperidin-1- yl)acetamide579.4 (M + H) 622

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2- ylmethyl)piperidin-4-yl)- 1-methyl-1H-imidazole-5-carboxamide 562.3 (M + H) 623

(R)-N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2- ylmethyl)piperidin-4-yl)- 2-methoxypropanamide 540.2(M + H) 624

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2- ylmethyl)piperidin-4-yl)- 2-morpholinoacetamide 581.3(M + H)

Example 625

4-(6-(4-(dimethylamino)-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of N,N-dimethyl-4-(pyridin-2-ylmethyl)piperidin-4-aminebis(2,2,2-trifluoroacetate) (Intermediate R29; 71 mg, 0.16 mmol),6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 30 mg, 0.11 mmol) and K₂CO_(3(s)) (73 mg, 0.53 mmol)in DMSO (1063 μL) was stirred for 1 h at 100° C. After cooling toambient temperature, the mixture was filtered, and the filtrate waspurified directly by C18 reverse phase chromatography (using 5-95%ACN/water with 0.1% TFA as the gradient eluent) to afford the titlecompound as the TFA salt. The TFA salt was suspended in MeOH (5 mL),eluted through a basic resin (Stratospheres Pl-HCO3) to cleanly affordthe title compound (15 mg, 29% yield). MS (apci) m/z=482.3 (M+H).

Example 626

2-(azetidin-3-yl)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)acetamide

Step 1: Preparation of tert-butyl3-(2-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)-2-oxoethyl)azetidine-1-carboxylate.A solution of4-(6-(4-amino-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P106; 41 mg, 0.09 mmol) and2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (21 mg, 0.1 mmol) inDCM (0.5 mL) was treated sequentially with DIEA (32 μL, 0.18 mmol) andHATU (41 mg, 0.11 mmol). The resulting mixture was stirred overnight atambient temperature then diluted with water and extracted with DCM (3×20mL). The combined organic extracts were dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The crude residue waspurified by silica chromatography (using 0-50% [20% MeOH in DCM] in DCMas the gradient eluent) to cleanly afford the title compound (59 mg,100% yield). MS (apci) m/z=651 (M+H).

Step 2: Preparation of2-(azetidin-3-yl)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)acetamide.A solution of tert-butyl3-(2-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)-2-oxoethyl)azetidine-1-carboxylate(59 mg, 0.091 mmol) in DCM (3.00 mL) was treated with TFA (3.00 mL, 39.2mmol). The resulting mixture was stirred for 1.5 h at ambienttemperature. The mixture was diluted with saturated NaHCO_(3(aq)) (3 mL)and extracted with DCM (3×5 mL). The combined organic extracts wereconcentrated in vacuo. The residue was purified by silica chromatography(using 0-50% [20% MeOH/DCM] in DCM followed by 0-50% MeOH in (20%MeOH/DCM) as the gradient eluent) to cleanly afford the title compound(10 mg, 20% yield). MS (apci) m/z=551.2 (M+H).

Example 627

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-2-(morpholin-2-yl)acetamide

Step 1: Preparation of tert-butyl2-(2-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)-2-oxoethyl)morpholine-4-carboxylate.A solution of4-(6-(4-amino-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P106; 32 mg, 0.07 mmol) and2-(4-(tert-butoxycarbonyl)morpholin-2-yl)acetic acid (19 mg, 0.08 mmol)in DCM (0.35 mL) was treated sequentially with DIEA (25 μL, 0.14 mmol)and HATU (32 mg, 0.085 mmol). The resulting mixture was stirredovernight at ambient temperature, then diluted with water and extractedwith DCM (3×15 mL). The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The cruderesidue was purified by silica chromatography (using 0-50% [20% MeOH inDCM] in DCM as the gradient eluent) to cleanly afford the title compound(48 mg, 100% yield). MS (apci) m/z=681 (M+H).

Step 2: Preparation ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-2-(morpholin-2-yl)acetamide.A solution of tert-butyl2-(2-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)-2-oxoethyl)morpholine-4-carboxylate(Step 1; 48 mg, 0.071 mmol) in DCM (300 μL) was treated with TFA (300μL, 3.92 mmol). The resulting mixture was stirred for 80 min at ambienttemperature. The resulting mixture was diluted with saturatedNaHCO_(3(aq)), and extracted with DCM (3×10 mL). The combined organicextracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated in vacuo. The crude residue was purified by silicachromatography (using 0-50% MeOH in [20% MeOH/DCM] as the gradienteluent) to cleanly afford the title compound (8 mg, 20% yield). MS(apci) m/z=581.25 (M+H).

Example 628

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-2-(4-ethylmorpholin-2-yl)acetamidebis(2,2,2-trifluoroacetate)

A solution ofN-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-2-(morpholin-2-yl)acetamide(Example 627; 6 mg, 0.01 mmol) in DCM (100 μL) was treated sequentiallywith acetaldehyde (2 μL, 0.03 mmol) and NaBH(AcO)₃ (11 mg, 0.052 mmol),and stirred for 2 d and 19 h at room temperature. The resulting mixturewas diluted with water (10 mL) and extracted with DCM (3×10 mL). Thecombined organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The crude residue was purified byC18 reverse phase chromatography (5-95% ACN:water with 0.1% TFA) toafford the title compound (0.831 mg, 13% yield). MS (apci) m/z=609.3(M+H).

Example 629

(2S,3R)-2-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-3-hydroxybutanamide

Step 1: Preparation of (9H-fluoren-9-yl)methyl((2S,3R)-1-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)-3-hydroxy-1-oxobutan-2-yl)carbamate.A solution of4-(6-(4-amino-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P106; 7.8 mg, 0.0172 mmol) in DCM (0.35 mL) was treatedsequentially with HATU (7.85 mg, 0.0206 mmol), DIEA (3.00 μL, 0.0172mmol) and (((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine (5.87 mg,0.0172 mmol). The resulting mixture was stirred for 3 d at ambienttemperature, then concentrated in vacuo to afford crude title compound(0.0172 mmol; assumed quantitative yield) which was carried directlyinto step 2. MS (apci) m/z=777.3 (M+H).

Step 2: Preparation of(2S,3R)-2-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-3-hydroxybutanamide.A solution of (9H-fluoren-9-yl)methyl((2S,3R)-1-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)-3-hydroxy-1-oxobutan-2-yl)carbamate(0.0172 mmol) in 1:1 v/v morpholine DCM (1 mL) was stirred for 3h atambient temperature, then concentrated and purified by reverse-phasechromatography (5 to 95% acetonitrile/water with 0.2% TFA) to yield thetitle product after freebasing with HCO₃ Stratosphere resin (5 mg, 52%yield). MS (apci) m/z=555.7 (M+H).

Example 630

(R)-2-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)propanamide

A solution of (9H-fluoren-9-yl)methyl(R)-(1-oxo-1-((4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)propan-2-yl)carbamatebis(2,2,2-trifluoroacetate) (Intermediate R39; 130 mg, 0.182 mmol) inDMF (0.3 mL) was treated with Cs₂CO_(3(s)) (270 mg, 0.829 mmol) and6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 46.8 mg, 0.166 mmol). The resulting mixture wasstirred overnight at 90° C. After cooling to ambient temperature, themixture was purified directly by C18 reverse phase chromatography (using5-95% ACN/water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was suspended in MeOH (5mL), eluted through a basic resin (Stratospheres Pl-HCO3) to cleanlyafford the title compound (30.2 mg, 35% yield). MS (apci) m/z=525.2(M+H).

The compounds in Table QQQ were prepared, worked up, purified and freebased using a similar method to that described in the synthesis of(R)-2-amino-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)propanamide(Example 630), replacing (9H-fluoren-9-yl)methyl(R)-(1-oxo-1-((4-(pyridin-2-ylmethyl)piperidin-4-yl)amino)propan-2-yl)carbamatebis(2,2,2-trifluoroacetate) (Intermediate R39) with the appropriateamine (1.0-1.5 equivalents). Reactions were monitored for completion byLCMS, and reaction durations were adjusted accordingly.

TABLE QQQ MS (apci) Ex # Structure Chemical Name m/z 631

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2- ylmethyl)piperidin-4- yl)-3- morpholinopropanamide595.3 (M + H) 632

(R)-2-amino-N-(1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-(pyridin-2- ylmethyl)piperidin-4- yl)-3-methylbutanamide 553.3 (M + H) 633

(S)-2-amino-N-(1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-(pyridin-2- ylmethyl)piperidin-4- yl)-3-methylbutanamide 553.3 (M + H)

Example 634

4-(6-(4-benzyl-4-(((2-hydroxyethyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P77, 10 mg, 0.0215 mmol) and 2-(methylamino)ethan-1-ol(13.0 mg, 0.173 mmol) in DCE (750 μL) was stirred for 1 h at ambienttemperature, then treated with NaBH(AcO)₃ (105.9 mg, 0.4997 mmol). Theresulting mixture was stirred for 4 d at ambient temperature, beforeintroducing additional 2-(methylamino)ethan-1-ol (13.0 mg, 0.173 mmol)and NaBH(AcO)₃ (105.9 mg, 0.4997 mmol). The resulting mixture wasstirred overnight at ambient temperature before diluting with DCM, andextracting with water (3×). The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), and filtered. The filtrate was purifieddirectly by silica chromatography (using 0-100% Hexanes/EtOAc as thegradient eluent) to afford the title compound (1.8 mg, 16% yield). MS(apci) m/z=525.25 (M+H).

Example 635

4-(6-(4-benzyl-4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P77, 10.5 mg, 0.0226 mmol) andN¹,N¹,N²-trimethylethane-1,2-diamine (24.1 mg, 0.236 mmol) in DCE (750μL) was stirred for 1 h at ambient temperature then treated withNaBH(AcO)₃ (75 mg, 0.354 mmol). The resulting mixture was stirredovernight at ambient temperature. The resulting mixture was diluted withwater, and extracted with DCM. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), and filtered. The filtrate was purifieddirectly by silica chromatography (using 0-50% DCM/MeOH as the gradienteluent) to afford the title compound (6.0 mg, 48% yield). MS (apci)m/z=552.3 (M+H).

Example 636

2-(((4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)(methyl)amino)-N,N-dimethylacetamide

A solution of4-(6-(4-benzyl-4-formylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P77, 11.4 mg, 0.0245 mmol) andN,N-dimethyl-2-(methylamino)acetamide (28.4 mg, 0.245 mmol) in DCE (750μL) was stirred for 2 h at ambient temperature then treated withNaBH(AcO)₃ (104 mg, 0.490 mmol). The resulting mixture was stirredovernight at ambient temperature. The resulting mixture was diluted withwater, and extracted with DCM. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), and filtered. The filtrate was purifieddirectly by silica chromatography (using 0-100% Hexanes/EtOAc as thegradient eluent) to afford the title compound (2.3 mg, 17% yield). MS(apci) m/z=566.25 (M+H).

Example 637

tert-butyl(S)-4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidin-4-yl)methyl)-3-methylpiperazine-1-carboxylate

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 45.6 mg, 0.0961 mmol) and tert-butyl(S)-3-methylpiperazine-1-carboxylate (96.22 mg, 0.4804 mmol) in DCE (1mL) was stirred for 30 min at ambient temperature before addingNaBH(AcO)₃ (122.2 mg, 0.5765 mmol). The resulting mixture was stirredfor 5 d at ambient temperature, then diluted with DCM, and washed withwater. The organic extracts were purified directly by silicachromatography (using 20-80% Hexanes/EtOAc as the gradient eluent) tocleanly provide the title compound (37.9 mg, 57% yield). MS (apci)m/z=659.3 (M+H).

The compounds in Table RRR were prepared using a similar method to thatdescribed in the synthesis of tert-butyl(S)-4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidin-4-yl)methyl)-3-methylpiperazine-1-carboxylate(Example 637), replacing 1 tert-butyl(S)-3-methylpiperazine-1-carboxylate with the appropriate amine andusing 4-6 equivalents of NaBH(AcO)₃. Reactions were monitored forcompletion by LCMS, as such reaction durations, both prior to and afterNaBH(AcO)₃ addition, were adjusted accordingly. Title compounds wereisolated following a similar aqueous work up with water or brine,followed by a chromatographic purification using an appropriate gradienteluent.

TABLE RRR MS (apci) Ex # Structure Chemical Name m/z 638

1-(5-(3-cyano-6- ethoxypyrazolo- [1,5-a]pyridin-4- yl)pyridin-2-yl)-N-isobutyl- 4-(((tetrahydro- 2H-pyran-4- yl)amino)methyl)-piperidine-4- carboxamide 560.3 (M + H) 639

tert-butyl 3-((1- (5-(3-cyano-6- ethoxypyrazolo- [1,5-a]pyridin-4-yl)pyridin-2-yl)-4- (isobutylcarbamoyl)- piperidin-4- yl)methyl)-3,6-diazabicyclo- [3.1.1]heptane-6- carboxylate 657.3 (M + H) 640

1-(5-(3-cyano-6- ethoxypyrazolo- [1,5-a]pyridin-4- yl)pyridin-2-yl)-N-isobutyl- 4-((6-methyl-2,6- diazaspiro[3.3]heptan-2-yl)methyl)piperidine-4- carboxamide 571.3 (M + H)

Example 641

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3-(dimethylamino)azetidin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 40 mg, 0.084 mmol) and N, N— dimethylazetidin-3-aminehydrochloride (42 mg, 0.42 mmol) in DCM (169 μL) was stirred for 30 minat ambient temperature. The resulting mixture was treated withNaBH(AcO)₃ (89 mg, 0.42 mmol), and stirred overnight at ambienttemperature. The reaction mixture was concentrated in vacuo. The cruderesidue was purified directly by C18 reverse phase chromatography (using5-95% water:ACN with 0.1% TFA as the gradient eluent). Fractionscontaining the desired product were diluted with 4:1 DCM:iPrOH, andextracted sequentially with saturated NaHCO_(3(aq)) (1×), and brine(2×). The organic extracts were dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to afford the title compound (23 mg,49% yield). MS (apci) m/z=559.4 (M+H).

The compounds in Table SSS were prepared using a similar method to thatdescribed in the synthesis of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3-(dimethylamino)azetidin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide(Example 641), replacing N, N-dimethylazetidin-3-amine hydrochloridewith 2-5 equivalents of the appropriate amine and 5-6 equivalents ofNaBH(AcO)₃. Reactions were monitored for completion by LCMS, as suchreaction durations, both prior to and after the NaBH(AcO)₃ addition,were adjusted accordingly. Title compounds were isolated following achromatographic purification using an appropriate gradient eluent. Forexamples in which an acid modifier (e.g. 0.1% TFA) was employed in thechromatographic purification conditions, a basic work up (e.g. anaqueous work up as described for Example 641; or use of a basic resin)was used to isolate the title compound.

TABLE SSS MS (apci) Ex # Structure Chemical Name m/z 642

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-((3,3- difluoropyrrolidin-1- yl)methyl)-N- isobutylpiperidine-4-carboxamide  566.3  (M + H) 643

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3- methoxyazetidin-1- yl)methyl)piperidine-4-carboxamide  546.3  (M + H) 644

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4- (((2- methoxyethyl)(methyl) amino)methyl)-piperidine-4-carboxamide  548.4  (M + H) 645

(S)-1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3- methoxypyrrolidin-1- yl)methyl)piperidine-4-carboxamide  560.4  (M + H) 646

(R)-1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3- methoxypyrrolidin-1- yl)methyl)piperidine-4-carboxamide  560.4  (M + H) 647

1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)-4-((3,3- difluoroazetidin-1- yl)methyl)-N- isobutylpiperidine-4-carboxamide 552.25, M + H 648

tert-butyl (S)-4-((1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4- (isobutylcarbamoyl)-piperidin-4-yl)methyl)-2- methylpiperazine-1- carboxylate 659.35, M + H649

tert-butyl (R)-4-((1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4- (isobutylcarbamoyl)-piperidin-4-yl)methyl)-2- methylpiperazine-1- carboxylate 659.3,  M + H650

tert-butyl 4-((1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4- (isobutyIcarbamoyl)piperidin-4-yl)methyl)- 2,2- dimethylpiperazine-1- carboxylate 673.3,  M +H

Example 651

(S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3-methylpiperazin-1-yl)methyl)piperidine-4-carboxamide

A solution of tert-butyl(S)-4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidin-4-yl)methyl)-2-methylpiperazine-1-carboxylate(Example 648; 27 mg, 0.0410 mmol) in DCM (1.5 mL) was treated with TFA(1.5 mL, 19 mmol). The resulting mixture was stirred at ambienttemperature until LCMS indicated complete consumption of startingBoc-protected compound, then concentrated in vacuo. The residue wasdiluted with EtOAc, and extracted with saturated NaHCO_(3(aq)) (2×).After back extracting the aqueous extracts with EtOAc, the organicextracts were combined, dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to cleanly afford the title compound (21.5 mg, 94%yield). MS (apci) m/z=559.3 (M+H).

Example 652

(S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((2-methylpiperazin-1-yl)methyl)piperidine-4-carboxamide

A solution of tert-butyl(S)-4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidin-4-yl)methyl)-3-methylpiperazine-1-carboxylate(Example 637; 35 mg, 0.053 mmol) in DCM (3.0 mL) was treated with TFA(1.5 mL, 19 mmol). The resulting mixture was stirred for 4 d at ambienttemperature, then concentrated in vacuo. The residue was diluted with4:1 DCM/iPrOH, and extracted with saturated NaHCO_(3(aq)). The organicextracts were combined, dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The crude residue was purified by C18 reversephase chromatography (using 0-70% ACN in water with 0.1% TFA as thegradient eluent). Fractions containing the desired product were dilutedwith 4:1 DCM:iPrOH, and extracted with saturated NaHCO_(3(aq)). Afterback extracting the aqueous extracts with 4:1 DCM:iPrOH, the organicextracts were combined, dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound to cleanly afford thetitle compound (3.3 mg, 9% yield). MS (apci) m/z=559.3 (M+H).

Example 653

4-((3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperidine-4-carboxamide

A solution of tert-butyl3-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidin-4-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate(Example 639; 15.7 mg, 0.0239 mmol) in DCM (2 mL) was treated with TFA(1.0 mL, 13 mmol). The resulting mixture was stirred for 30 min atambient temperature, then concentrated in vacuo. The residue was dilutedwith 4:1 DCM:iPrOH, and extracted with saturated NaHCO_(3(aq)) (2×).After back extracting the aqueous extracts with 4:1 DCM:iPrOH, theorganic extracts were combined, dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo to cleanly afford the title compound(13.9 mg, 100% yield). MS (apci) m/z=557.3 (M+H).

Example 654

(R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethyl-3-methylpiperazin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide

Step 1: Preparation of(R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3-methylpiperazin-1-yl)methyl)piperidine-4-carboxamidebis(2,2,2-trifluoroacetate). A mixture of tert-butyl(R)-4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidin-4-yl)methyl)-2-methylpiperazine-1-carboxylate(Example 649; 6.3 mg, 0.0096 mmol) in DCM (0.5 mL) was treated with TFA(0.1 mL, 1.3 mmol). The resulting mixture was stirred for 1 h at ambienttemperature before concentrating the mixture in vacuo to afford thetitle compound (5.3 mg, quantitative yield). MS (apci) m/z=559.3 (M+H).

Step 2: Preparation of(R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3-methylpiperazin-1-yl)methyl)piperidine-4-carboxamide.A solution of(R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3-methylpiperazin-1-yl)methyl)piperidine-4-carboxamide(5.3 mg, 0.00949 mmol) in DCM (0.61 μL) was treated with acetaldehyde(0.550 μL, 0.0190 mmol) and NaBH(AcO)₃ (4.02 mg, 0.0190 mmol), andstirred overnight at room temperature. The resulting mixture was dilutedwith 4:1 DCM:iPrOH, and extracted with saturated NaHCO_(3(aq))., andfiltered through PS frit. The organic filtrate was concentrated in vacuoto cleanly afford the title compound (4.4 mg, 79% yield). MS (apci)m/z=587.3 (M+H).

Example 655

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethyl-3,3-dimethylpiperazin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide

Step 1: Preparation of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,3-dimethylpiperazin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamidebis(2,2,2-trifluoroacetate). A mixture of tert-butyl tert-butyl4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(isobutylcarbamoyl)piperidin-4-yl)methyl)-2,2-dimethylpiperazine-1-carboxylate(Example 650; 7.7 mg, 0.011 mmol) in DCM (0.5 mL) was treated with TFA(0.1 mL, 1.3 mmol). The resulting mixture was stirred for 1 h at ambienttemperature before concentrating the mixture in vacuo to afford thetitle compound (6.6 mg, quantitative yield). MS (apci) m/z=573.4 (M+H).

Step 2: Preparation of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethyl-3,3-dimethylpiperazin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide.A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,3-dimethylpiperazin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide(6.6 mg, 0.0115 mmol) in DCM (0.73 μL) was treated with acetaldehyde(0.668 μL, 0.0230 mmol) and NaBH(AcO)₃ (4.88 mg, 0.0230 mmol), andstirred overnight at room temperature. The resulting mixture waspurified directly by silica chromatography (using 0-100% DCM/[10%MeOH/1% NH₄OH in DCM] as the gradient eluent) to cleanly afford thetitle compound (3.8 mg, 55% yield). MS (apci) m/z=601.3 (M+H).

Example 656

(S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((3,4-dimethylpiperazin-1-yl)methyl)-N-isobutylpiperidine-4-carboxamide

A solution of(S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((3-methylpiperazin-1-yl)methyl)piperidine-4-carboxamide(Example 651; 23.6 mg, 0.04224 mmol) in DCE (1000 μL) was treated withformaldehyde (37 wt. % in water with 5-15% MeOH stabilizer; 17.14 mg,0.2112 mmol), then stirred for 45 min at ambient temperature beforeadding NaBH(AcO)₃ (53.71 mg, 0.2534 mmol). The resulting mixture wasstirred for 3 d at room temperature. The reaction mixture was dilutedwith acetone, and concentrated in vacuo. The residue was dissolved inDCM, and washed with water. The organic extracts were purified directlyby silica chromatography (using 0-100% [10% MeOH+1% NH₄OH] in DCM as thegradient eluent) to cleanly afford the title compound (16.2 mg, 67%yield). MS (apci) m/z=575.3 (M+H).

Example 657

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)-N-isobutylpiperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide(Intermediate P76, 62.8 mg, 0.132 mmol) in 1:1 DCM:MeOH (1.3 mL) wastreated with NaBH₄ (98%; 50.1 mg, 1.32 mmol), stirred overnight at roomtemperature, and then concentrated in vacuo. The residue was dilutedwith 4:1 DCM:iPrOH, and extracted with saturated NaHCO_(3(aq)). Theorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to cleanly afford the title compound (44.4 mg, 70%yield). MS (apci) m/z=477.3 (M+H).

Example 658

Ethyl1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-4-carboxylate

A slurry of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 76 mg, 0.269 mmol), ethyl4-(hydroxymethyl)piperidine-4-carboxylate hydrochloride (IntermediateR42; 84.1 mg, 0.323 mmol), and DIEA (141 μL, 0.808 mmol) in DMSO (538μL) was stirred for 2 d at 90° C. After cooling to ambient temperature,the mixture was purified directly by C18 reverse phase chromatography(using 5-50% ACN/water as the gradient eluent). This allowed for theclean separation and isolation of the title compound (35.2 mg, 29%yield; MS (apci) m/z=450.2 (M+H)) and another product1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-4-carboxylicacid (Intermediate P156; 7.4 mg, 7% yield):

Example 659

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-((2-morpholinoethoxy)methyl)piperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-morpholinoethoxy)methyl)piperidine-4-carboxylicacid dihydrochloride (Intermediate P107; 25 mg, 0.044 mmol), DIEA (32.6μL, 0.187 mmol), HATU (35.6 mg, 0.0935 mmol) and isobutylamine (13.9 μL,0.140 mmol) in DMF (1.0 mL) was stirred for 5 h at ambient temperature.The mixture was concentrated in vacuo, and purified directly by C18reverse phase chromatography (5 to 95% acetonitrile in water) to cleanlyafford the title compound (6 mg, 22% yield). MS (apci) m/z=590.3 (M+H).

Example 660

1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-(dimethylamino)ethoxy)methyl)-N-isobutylpiperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((2-(dimethylamino)ethoxy)methyl)piperidine-4-carboxylicacid dihydrochloride (Intermediate P109; 22 mg, 0.0447 mmol), DIEA (31.1μL, 0.179 mmol), HATU (34.0 mg, 0.0893 mmol) and isobutylamine (13.4 μL,0.134 mmol) in DMF (1.0 mL) was stirred for 15 h at ambient temperature.The mixture was concentrated in vacuo, and purified directly by C18reverse phase chromatography (5 to 95% acetonitrile in water) to cleanlyafford the title compound (4 mg, 16% yield). MS (apci) m/z=548.3 (M+H).

Example 661

Tert-butyl(7-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl)carbamate

A slurry of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 100 mg, 0.354 mmol), tert-butyl(7-azaspiro[3.5]nonan-2-yl)carbamate (102 mg, 0.425 mmol), and DIEA (185μL, 1.06 mmol) in DMSO (1417 μL) was stirred for 18 h at 90° C. Aftercooling to ambient temperature, the mixture was poured into water (12mL) while stirring. The resulting suspension was vacuum filtered, andthe solids were rinsed sequentially with water (3×15 mL) and heptane(3×5 mL), then dried in vacuo to cleanly afford the title compound (175mg, 98% yield). MS (apci) m/z=503.2 (M+H).

Example 662

N-(1-(4-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-((dimethylamino)methyl)piperidin-4-yl)-3-methylbutanamide

A solution of4-(4-(4-amino-4-((dimethylamino)methyl)piperidin-1-yl)phenyl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P114; 35.7 mg, 0.0853 mmol) in DCM (6.6 μL) was treatedwith TEA (59.4 μL, 0.426 mmol) and isovaleryl chloride (20.8 μL, 0.171mmol). The resulting mixture was stirred for 30 min at ambienttemperature, and then concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA asthe gradient eluent). Fractions containing desired product werecombined, and partitioned between 4:1 DCM:iPrOH, and saturatedNaHCO_(3(aq)). The organic extracts were separated, and sequentiallydried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The slightly impure product residue was purified by silicachromatography (using 1-30% DCM-MeOH with 2% NH₄OH as the gradienteluent) to cleanly afford the title compound (8 mg, 17% yield). MS(apci) m/z=503.3 (M+H).

Example 663

4-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yldimethylcarbamate

A slurry of 3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yldimethylcarbamate (Intermediate P115; 69.4 mg, 0.213 mmol), tert-butyl(4-methylpiperidin-4-yl)carbamate (114 mg, 0.533 mmol) and DIEA (186 μL,1.07 mmol) in DMSO (3 mL) was stirred for 2 h at 90° C. After cooling toambient temperature, the mixture was diluted with water and extractedwith EtOAc (3×). The combined organic extracts were washed sequentiallywith water (2×) and brine. The aqueous extracts were combined,neutralized (pH 6-7) with the addition 6 M HCl_((aq)), and thenextracted with EtOAc (2×). The organic extracts from the neutralizationwere combined, and concentrated in vacuo. The crude residue was purifiedby silica chromatography (using 30-90% Hexanes/EtOAc as the gradienteluent), resulting in the clean isolation of4-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yldimethylcarbamate (45.3 mg), along with mixed fractions containing both4-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yldimethylcarbamate and the desired tert-butyl(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate.The mixed fractions were combined and concentrated in vacuo. The residuewas dissolved in DCM (500 μL), and treated with DIEA (100 μL, 0.57 mmol)and dimethylcarbamyl chloride (52 μL, 0.57 mmol). The resulting mixturewas stirred for a total of 5 d, supplementing with additionaldimethylcarbamyl chloride (52 μL, 0.57 mmol) after the initial 24 h. Theresulting mixture was washed sequentially with water and 2 MNaOH_((aq)). The organic extracts were purified directly by silicachromatography (using 50-90% Hexanes/EtOAc as the gradient eluent) tocleanly afford the title compound (74.8 mg, 66% yield). MS (apci)m/z=520.2 (M+H).

Example 664

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yldimethylcarbamate

A solution of4-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yldimethylcarbamate (Example 663; 70 mg, 0.135 mmol) in DCM (3 mL) wastreated with TFA 1.5 mL, 19 mmol). The resulting mixture was stirred for30 min at ambient temperature before concentrating in vacuo. The residuewas diluted with DCM, and washed with saturated NaHCO_(3(aq)). Afterback extracting the aqueous extracts with 4:1 DCM:iPrOH, the organicextracts were combined, dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to cleanly afford the title compound (25.2 mg, 45%yield). MS (apci) m/z=420.2 (M+H).

Example 665

3-cyano-4-(6-(4-((isopropoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yldimethylcarbamate

A mixture of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yldimethylcarbamate (Example 664; 13.6 mg, 0.0324 mmol) and DIEA (22.6 μL,0.130 mmol) in DCM (500 μL) was treated with isopropyl carbonochloridate(4.77 mg, 0.0389 mmol). The resulting mixture was stirred for 1 h atambient temperature, and was purified directly by silica chromatography(using 0-100% Hexanes/EtOAc as the gradient eluent) to cleanly affordthe title compound (11.5 mg, 69% yield). MS (apci) m/z=506.2 (M+H).

Example 666

Isopropyl(1-(5-(6-(2-(1H-imidazol-1-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A mixture of6-(2-(1H-imidazol-1-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P116; 12 mg, 0.034 mmol), isopropyl(4-methylpiperidin-4-yl)carbamate hydrochloride (Intermediate R19, partB; 16 mg, 0.069 mmol) and Cs₂CO_(3(s)) (112 mg, 0.34 mmol) in DMSO (1.5mL) was stirred overnight at 100° C. Subsequently, additional isopropyl(4-methylpiperidin-4-yl)carbamate hydrochloride (Intermediate R19, partB; 16 mg, 0.069 mmol) was introduced, and the resulting mixture wasstirred overnight at 100° C. After cooling to ambient temperature, thereaction mixture was diluted with water, and washed sequentially withDCM (4×) and 4:1 DCM:iPrOH. The combined organic extracts were driedover anhydrous Na₂SO_(4(s)), and filtered. The filtrate was purifieddirectly by silica chromatography (using 0-50% DCM/MeOH with 1% NH₄OH asthe gradient eluent). Fractions containing the desired compound werecombined, concentrated in vacuo, then partitioned between water and DCM.The organic extracts were separated, and concentrated in vacuo tocleanly afford the title compound (7.2 mg, 34% yield). MS (apci)m/z=529.2 (M+H).

Example 667

Isopropyl(1-(5-(3-cyano-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of4-(6-fluoropyridin-3-yl)-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P117; 26.0 mg, 0.0746 mmol) in DMA (1.0 mL) was treatedwith isopropyl (4-methylpiperidin-4-yl)carbamate hydrochloride(Intermediate R19; 35.34 mg, 0.1493 mmol) and TEA (104.1 μL, 0.7464mmol) was stirred for 60 h at 60° C. After cooling to ambienttemperature, the reaction mixture purified directly by C18 reverse phasechromatography (using 0-50% water/ACN with 0.1% TFA as the gradienteluent). Fractions containing the desired product were combined,concentrated in vacuo to remove the ACN, then partitioned betweensaturated NaHCO_(3(aq)) and 4:1 DCM:iPrOH. The organic extracts wereconcentrated in vacuo to afford the title compound (8.7 mg, 18% yield).MS (apci) m/z=529.2 (M+H).

Example 668

Isopropyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A mixture of4-(6-fluoropyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P79, 22.1 mg, 0.0602 mmol), isopropyl(4-methylpiperidin-4-yl)carbamate hydrochloride (Intermediate R19; 28.5mg, 0.120 mmol) and Cs₂CO_(3(s)) (196 mg, 0.602 mmol) in DMSO (1.5 mL)was stirred overnight at 100° C. Subsequently, additional isopropyl(4-methylpiperidin-4-yl)carbamate hydrochloride (Intermediate R19; 28.5mg, 0.120 mmol) was introduced, and the resulting mixture was stirredovernight at 100° C. After cooling to ambient temperature, the reactionmixture was diluted with water, and washed sequentially with DCM (4×)and 4:1 DCM:iPrOH. The combined organic extracts were dried overanhydrous Na₂SO_(4(s)), and filtered. The filtrate was purified directlyby silica chromatography (using 0-50% water/ACN with 0.1% TFA as thegradient eluent). Fractions containing the desired product werecombined, concentrated in vacuo to remove the ACN, then partitionedbetween saturated NaHCO_(3(aq)) and 4:1 DCM:iPrOH. The organic extractswere concentrated in vacuo to afford the title compound (2.7 mg, 8%yield). MS (apci) m/z=548.2 (M+H).

Example 669

Isobutyl(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P119; 41 mg, 0.060 mmol) inDCM (500 μL) was treated sequentially with DIEA (30.9 μL, 0.178 mmol)and isobutyl chloroformate (13.9 μL, 0.107 mmol). The resulting mixturewas stirred for 24 h at ambient temperature. The reaction mixture wasdiluted with 4:1 DCM:iPrOH, and extracted sequentially with water andbrine. After back extracting the aqueous extracts with 4:1 DCM:iPrOH,the organic extracts were combined, dried over anhydrous Na₂SO_(4(s)),then concentrated in vacuo. The residue was purified by C18 reversephase chromatography (using 5-95% water:ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in MeOH (5 mL), and eluted through a basic resin(Stratospheres P1-HCO3) to cleanly afford the title compound (11.2 mg,33% yield). MS (apci) m/z=562.3 (M+H).

Example 670

N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-3-methylbutanamide

A solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P119; 40 mg, 0.058 mmol) inDCM (578 μL) was treated sequentially with DIEA (30.2 μL, 0.173 mmol),HATU (39.5 mg, 0.104 mmol) and isovaleric acid (10.5 μL, 0.0953 mmol).The resulting mixture was stirred overnight at ambient temperature, thenpurified directly by C18 reverse phase chromatography (using 5-95%ACN/water with 0.1% TFA as the gradient eluent) to afford the TFA saltof the title compound. The TFA salt was dissolved in MeOH (1 mL), andeluted through a basic resin (Stratospheres P1-HCO3) to cleanly affordthe title compound (19 mg, 60% yield). MS (apci) m/z=546.2 (M+H).

Example 671

(S)-1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3-methylbutan-2-yl)piperidine-4-carboxamide

A solution of1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid (Intermediate P121; 40 mg, 0.0815 mmol) in DCM (544 μL) was treatedsequentially with DIEA (28.4 μL, 0.163 mmol), HATU (37.2 mg, 0.0978mmol) and (S)-(+)-3-methyl-2-butylamine (9.48 μL, 0.0815 mmol). Theresulting mixture was stirred for 16 h at ambient temperature, thenconcentrated in vacuo. The crude residue was purified by silicachromatography (using 5-95% ACN/water with 0.1% TFA as the gradienteluent) to afford the TFA salt of the title compound. The TFA salt wasdissolved in MeOH (5 mL), and eluted through a basic resin(Stratospheres P1-HCO3) to cleanly afford the title compound (21 mg, 46%yield). MS (apci) m/z=560.4 (M+H).

Example 672

(R)-1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3-methylbutan-2-yl)piperidine-4-carboxamide

The title compound (22.5 mg, 47% yield) was prepared and purified usinga similar procedure to that described for(S)-1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3-methylbutan-2-yl)piperidine-4-carboxamide(Example 671), replacing (S)-(+)-3-methyl-2-butylamine (1 equiv) with(R)-(−)-3-methyl-2-butylamine (1.1 equiv). MS (apci) m/z=560.4 (M+H).

Example 673

1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-4-methylpiperidine-4-carboxamide

The title compound (26.7 mg, 60% yield) was prepared and purified usinga similar procedure to that described for(S)-1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3-methylbutan-2-yl)piperidine-4-carboxamide(Example 671), replacing (S)-(+)-3-methyl-2-butylamine withisobutylamine. MS (apci) m/z=546.3 (M+H).

Example 674

tert-butyl(S)-2-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate

A solution of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75, 100 mg, 0.205 mmol) and Cs₂CO_(3(s)) (134 mg, 0.410mmol) in DMF (1366 μL) was treated with tert-butyl(S)-2-(bromomethyl)morpholine-4-carboxylate (57.4 mg 0.205 mmol) wasstirred overnight at 60° C. After cooling to ambient temperature, thereaction mixture was diluted with water (10 mL), and extracted withEtOAc (4×10 mL). The combined organic extracts were washed sequentiallywith water (3×10 mL) and brine (10 mL). The organic extracts were driedover anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. Theresidue was purified twice by silica chromatography (first using 0-100%[10% MeOH with 1% NH₄OH in DCM]/DCM, and again using a stepped gradientof 0-100% EtOAc/Hexanes followed by 0-10% EtOAc/MeOH as the gradienteluent) to afford the title compound (130 mg, 84% yield). MS (apci)m/z=687.2 (M+H).

Example 675

tert-butyl(R)-2-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate

The title compound (110 mg, 78% yield) was prepared, worked up andpurified using a similar procedure to that described for tert-butyl(S)-2-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Example 674), replacing tert-butyl(S)-2-(bromomethyl)morpholine-4-carboxylate with tert-butyl(R)-2-(bromomethyl)morpholine-4-carboxylate. MS (apci) m/z=687.2 (M+H).

Example 676

(R)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

A solution of tert-butyl(R)-2-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Example 675; 110 mg, 0.160 mmol) in DCM (10.2 μL) and TFA (12.2 μL,0.160 mmol) was stirred for 1 h at ambient temperature. The reactionmixture was concentrated in vacuo, and the residue was dissolved in MeOH(3 mL). A portion of the methanolic solution (2 mL) was concentrated invacuo to afford the TFA salt of the title compound,(R)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamidebis(2,2,2-trifluoroacetate) (63 mg, 48% yield; MS (apci) m/z=587.2(M+H)). The remaining portion of the methanolic solution (1 mL) waspurified by C18 reverse phase chromatography (using 5-95% ACN in waterwith 0.2% TFA as the gradient eluent). Fractions containing the desiredcompound were combined, then sequentially, concentrated in vacuo,dissolved in MeOH (5 mL), and eluted through a basic resin(Stratospheres MP-HCO3) to cleanly afford the title compound (9.3 mg,10% yield). MS (apci) m/z=587.2 (M+H).

Example 677

(S)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

The title compound (8.2 mg, 7% yield), along with the TFA salt of thetitle compound(S)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamidebis(2,2,2-trifluoroacetate) (78 mg, 51% yield) were prepared, separatedand purified using a similar procedure to that described for(R)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Example 676), replacing tert-butyl(R)-2-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Example 675; with tert-butyl(S)-2-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazol o [1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate (Example 674). MS (apci)m/z=587.2 (M+H).

Example 678

(S)-3-chloro-N-(1-(5-(3-cyano-6-((4-methylmorpholin-2-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

A solution of(S)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamidebis(2,2,2-trifluoroacetate) (Example 677, TFA salt; 78 mg, 0.0957 mmol)in DCM (957 μL) was treated with formaldehyde (35 wt. % in water with5-15% MeOH stabilizer; 38 μL, 0.478), and NaBH(AcO)₃ (203 mg, 0.957mmol), and stirred for 1 h at room temperature. The reaction mixture waspurified directly by C18 reverse phase chromatography (using 5-95% ACNin water with 0.2% TFA as the gradient eluent). Fractions containing thedesired compound were combined, then sequentially, concentrated invacuo, dissolved in MeOH (5 mL), and eluted through a basic resin(Stratospheres MP-HCO3) to cleanly afford the title compound (31 mg, 54%yield). MS (apci) m/z=601.2 (M+H).

Example 679

(R)-3-chloro-N-(1-(5-(3-cyano-6-((4-methylmorpholin-2-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

The title compound (21 mg, 45% yield) was prepared and purified using asimilar procedure to that described for(S)-3-chloro-N-(1-(5-(3-cyano-6-((4-methylmorpholin-2-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Example 678), replacing(S)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamidebis(2,2,2-trifluoroacetate) (Example 677) with(R)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamidebis(2,2,2-trifluoroacetate) (Example 676). MS (apci) m/z=601.2 (M+H).

Example 680

3-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl3-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate.A mixture of3-chloro-N-(1-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide(Intermediate P75, 200 mg, 0.410 mmol), tert-butyl3-(bromomethyl)-3-fluoroazetidine-1-carboxylate (220 mg, 0.820 mmol) andCs₂CO_(3(s)) (160 mg, 0.492 mmol) in DMA (4099 μL) was stirred overnightat 60° C. Subsequently, additional Cs₂CO_(3(s)) (160 mg, 0.492 mmol) wasintroduced, and the reaction mixture was stirred overnight again at 60°C. After cooling to ambient temperature, the reaction mixture waspartitioned between 4:1 DCM:IPA and water through a PS Frit rinsing with4:1 DCM:IPA (3×). The combined organic extracts were concentrated invacuo, and purified by silica chromatography (using a stepped gradientof 0-100% EtOAc/Hexanes as the gradient eluent) to afford the titlecompound contaminated with DMA (277 mg, quantitative yield assumed). MS(apci) m/z=675.3 (M+H).

Step 2: Preparation of3-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide

A solution of tert-butyl3-(((4-(6-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(277 mg, 0.410 mmol) in DMA (˜0.5 mL; a solution that carried throughthe column) was treated with TFA (1106 μL, 14.4 mmol) and stirred for 60h at ambient temperature. The reaction mixture was diluted with DCM andbrine, then neutralized to pH 7 with 2 N NaOH_((aq)). The resultingbiphasic mixture was passed through a PS Frit, and the organics wereconcentrated in vacuo. The crude residue was purified by silicachromatography (using 0-15% MeOH in EtOAc with 0.2% NH₄OH as thegradient eluent) to cleanly afford the title compound (79 mg, 34% yield,over 2 steps). MS (apci) m/z=575.2 (M+H).

Example 681

2-chloro-N-(1-(6-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-3-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of4-(5-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P124; 4.8 mg, 0.010 mmol) in DCM (0.2 mL)was treated sequentially with 2-chloro-6-methylbenzoic acid (3.5 mg,0.021 mmol), DIEA (27 μL, 0.16 mmol), HATU (7.9 mg, 0.021 mmol). Theresulting mixture was stirred for 17 h at ambient temperature, beforediluting with water (10 mL) and extracting with DCM (2×10 mL). Thecombined organic extracts were dried over anhydrous MgSO_(4(s)),filtered and concentrated in vacuo. The crude residue was purified byC18 reverse phase chromatography (using 5-95% ACN in water with 0.2% TFAas the gradient eluent) to afford the TFA salt of the title compound.The TFA salt was dissolved in MeOH (1 mL), and eluted through a basicresin (Stratospheres SPE MP-HCO3) to cleanly afford the title compound(3.5 mg, 55% yield). MS (apci) m/z=614.2 (M+H).

Example 682

2-chloro-N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of4-(2-(4-amino-4-methylpiperidin-1-yl)pyrimidin-5-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P131; 22.7 mg, 0.0329 mmol) inDCM (579 μL) was treated with 2-chloro-6-methylbenzoic acid (25.1 mg,0.147 mmol), DIEA (15 μL, 0.087 mmol) and HATU (13 mg, 0.035 mmol). Theresulting mixture was stirred for 3 h at ambient temperature, wasconcentrated in vacuo. The residue was purified directly by silicachromatography (0-100% EtOAc in Hexanes followed by 0-10% MeOH in DCM).Persistent impurities required a second silica chromatography (0-10%MeOH in DCM with 0-0.1% NH₄OH) to cleanly afford the title compound (2.8mg, 9% yield). MS (apci) m/z=615.2 (M+H).

Example 683

N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

The title compound (12.34 mg, 42% yield) was prepared and purified usinga similar procedure to that described forN-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 682), replacing 2-chloro-6-methylbenzoic acid with5-fluoro-2-methylbenzoic acid. MS (apci) m/z=599.3 (M+H).

Example 684

2-chloro-N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamide

The title compound (14 mg, 46% yield) was prepared and purified using asimilar procedure to that described forN-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide(Example 682), except 2-chloro-6-methylbenzoic acid was replaced with2-chloro-5-fluorobenzoic acid and the reaction was allowed to stirovernight at ambient temperature before the work up and purificationrequired only a single silica chromatographic separation (using 0-100%EtOAc in Hex then 0-10% MeOH in EtOAc as the gradient eluent). MS (apci)m/z=619.2 (M+H).

Example 685

2-chloro-N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

In a sealed vessel, a solution of4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P41, 18 mg, 0.058 mmol) in dioxane (0.5 mL) was treatedsequentially with water (0.15 mL), Cs₂CO_(3(s)) (57 mg, 0.17 mmol), and2-chloro-6-methyl-N-(4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperidin-4-yl)benzamide(Intermediate P125; 38 mg, 0.058 mmol). The resulting mixture wassparged with N_(2(g)) for 5 min then treated with X-phos (11 mg, 0.023mmol) and Pd₂(dba)₃ (5.3 mg, 0.0058 mmol). After sparging with N_(2(g))for 5 min, the vessel was sealed, and the resulting mixture was stirredfor 17 h at 80° C. After cooling to ambient temperature, the resultingsuspension was diluted with water (10 mL) and extracted with DCM (2×10mL). The combined organic extracts were dried over anhydrousMgSO_(4(s)), filtered and concentrated in vacuo. The crude residue waspurified by C18 reverse phase chromatography (using 5-95% ACN in waterwith 0.1% TFA as the gradient eluent) to afford the TFA salt of thetitle compound. The TFA salt was dissolved in MeOH (1 mL), and elutedthrough a basic resin (Stratospheres SPE MP-HCO3) to cleanly afford thetitle compound (3.6 mg, 11% yield). MS (apci) m/z=574.2 (M+H); 596.2(M+Na).

Example 686

2-chloro-N-(1-(5-(3-cyano-6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution ofN-(1-(5-(6-(2-aminoethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-2-chloro-6-methylbenzamidebis(2,2,2-trifluoroacetate) (Intermediate P152; 80 mg, 0.103 mmol) inDCM (66 μL) was treated with formaldehyde (37% aq, 19.3 μL, 0.517 mmol)and NaBH(AcO)₃ (110 mg, 0.517 mmol), then stirred overnight at ambienttemperature. The resulting mixture was partitioned between 4:1 DCM:iPrOHand saturated NaHCO_(3(aq)), and eluted through a PS Frit. The organicfiltrate was concentrated in vacuo to cleanly afford the title compound(12.6 mg, 21% yield). MS (apci) m/z=573.3 (M+H).

Example 687

2-chloro-N-(1-(5-(3-cyano-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

In a pressure tube, a mixture of6-((1-methyl-1H-imidazol-4-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P145; 54 mg, 0.142 mmol),2-chloro-N-(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Intermediate R48; 54.0 mg, 0.142 mmol), 2 M K₃PO_(4(aq)) (214 μL, 0.427mmol), X-phos (13.6 mg, 0.0285 mmol) and Pd₂(dba)₃ (6.52 mg, 0.00712mmol) in dioxane (1.0 mL) was sparged with Ar_((g)) for 10 min, and thenthe vessel was sealed. The reaction mixture was stirred overnight at 80°C. After cooling to ambient temperature, the reaction mixture wasdiluted with DCM, and extracted sequentially with water (3×) and brine(1×). The organic extracts were purified directly by silicachromatography (0-100% EtOAc/Hexanes), and then by C18 reverse phasechromatography (5-95% ACN in water with 0.1% TFA) to cleanly provide thetitle compound (12.5 mg, 14.7% yield). MS (apci) m/z=596.2 (M+H).

Example 688

(R)-2-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of tert-butyl(R)-2-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P148; 40.3 mg, 0.0575 mmol) in DCM (1 mL) and TFA (500 μL,6.53 mmol) was stirred for 2 h at ambient temperature. Reaction was thenconcentrated down and purified by silica chromatography (using 0-100%[10% MeOH in DCM WITH 1% NH₄OH]/DCM as the gradient eluent) to cleanlyafford the title compound (21.3 mg, 10% yield). MS (apci) m/z=601.2(M+H).

Example 689

(R)-2-chloro-N-(1-(5-(3-cyano-6-((4-ethylmorpholin-2-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of(R)-2-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Example 688; 12 mg, 0.02 mmol) in DCM (100 μL) was treated withacetaldehyde (1 μL, 0.02 mmol) and NaBH(AcO)₃ (4 mg, 0.02 mmol), andstirred for 20 h at ambient temperature. The resulting mixture wasconcentrated in vacuo, and the residue was purified by C18 reverse phasechromatography (using 5-95% water-ACN with 0.1% TFA as the gradienteluent) to afford the TFA salt of the title compound. The TFA salt waspartitioned between 4:1 DCM:iPrOH and saturated NaHCO_(3(aq)). Theorganic extracts were separated, dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo to cleanly afford the title compound(2.25 mg, 18% yield). MS (apci) m/z=629.2 (M+H).

Example 690

(S)-2-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

The title compound (26.2 mg, quantitative yield) was prepared andpurified using a similar procedure to that described for(R)-2-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Example 688), replacing tert-butyl(R)-2-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P148; 0.0575 mmol) with of tert-butyl(S)-2-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P150; 0.164 mmol) and using 1 mL TFA. MS (apci) m/z=601.2(M+H).

Example 691

(S)-2-chloro-N-(1-(5-(3-cyano-6-((4-ethylmorpholin-2-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of(S)-2-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Example 690; 19.5 mg, 0.0324 mmol) in DCM (200 μL) was treated withacetaldehyde (1.88 μL, 0.0649 mmol) and NaBH(AcO)₃ (13.8 mg, 0.0649mmol), and stirred overnight at ambient temperature. The resultingmixture was partitioned between 4:1 DCM:iPrOH and saturatedNaHCO_(3(aq)), and eluted through a PS Frit. The combined organicfiltrates were concentrated in vacuo to cleanly afford the titlecompound (9.4 mg, 46% yield). MS (apci) m/z=629.3 (M+H).

Example 692

N-(1-(5-(6-(2-(azetidin-1-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-2-chloro-6-methylbenzamide

In a pressure tube, a mixture of6-(2-(azetidin-1-yl)ethoxy)-4-bromopyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P126; 26.4 mg, 0.0822 mmol),2-chloro-6-methyl-N-(4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperidin-4-yl)benzamide(Intermediate R49; 53 mg, 0.0822 mmol), Pd(PPh₃)₄ (2.85 mg, 0.00247mmol) and 2 M Na₂CO_(3(aq)) (247 μL, 0.493 mmol) in dioxane (2 mL) wassparged with Ar_((g)). The vessel was sealed, and the mixture wasstirred for 2 h at 80° C. After cooling to ambient temperature, thereaction mixture was diluted with water (10 mL) and extracted with 4:1DCM:iPrOH (5×10 mL). The combined organic extracts were concentrated invacuo, and the residue was purified by silica chromatography (using0-10% MeOH in DCM as the gradient eluent) to cleanly afford the titlecompound (17 mg, 35% yield). MS (apci), m/z=585.3 (M+H).

Example 693

2-chloro-N-(1-(5-(3-cyano-6-(2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

In a pressure tube, a mixture of6-(2-(pyrrolidin-1-yl)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P143; 68 mg, 0.178 mmol),2-chloro-N-(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Intermediate R48; 67.5 mg, 0.178 mmol), 2 M K₃PO_(4(aq)) (267 μL, 0.534mmol), X-phos (17.0 mg, 0.0356 mmol) and Pd₂(dba)₃ (8.14 mg, 0.00889mmol) in dioxane (889 μL) was sparged with Ar_((g)) for 3 min, and thenthe vessel was sealed. The reaction mixture was stirred overnight at 80°C. After cooling to ambient temperature, the reaction mixture wasdiluted with water, and extracted with DCM (4×). The combined organicextracts were washed with brine (1×), dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The residue was purified by silicachromatography (using 0-20% MeOH in DCM as the gradient eluent) tocleanly afford the title compound (2.04 mg, 2% yield). MS (apci),m/z=599.2 (M+H).

Example 694

2-chloro-N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P129; 20 mg, 0.0290 mmol),HATU (13.2 mg, 0.0348 mmol) and 2-chloro-6-methylbenzoic acid (5.43 mg,0.0319 mmol) in DCM (579 μL) was treated with DIEA (15.2 μL, 0.0869mmol). The resulting mixture was stirred overnight at ambienttemperature, before introducing additional HATU (3.4 mg, 0.015 mmol) andDIEA (5 μL, 0.029 mmol). The resulting mixture was stirred for 60 h atambient temperature. The reaction mixture was purified directly bysilica chromatography (using 0-10% MeOH in EtOAc with 0.2% NH₄OH as thegradient eluent) to cleanly afford the title compound (2.87 mg, 16%yield). MS (apci) m/z=615.4 (M+H).

Example 695

3-chloro-N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)picolinamide

A solution of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P129; 20 mg, 0.0290 mmol),HATU (13 mg, 0.035 mmol) and 3-chloropicolinic acid (5.0 mg, 0.032 mmol)in DCM (579 μL) was treated with DIEA (15 μL, 0.087 mmol). The resultingmixture was stirred overnight at ambient temperature, was purifieddirectly by silica chromatography (using 0-10% MeOH in EtOAc with 0.2%NH₄OH as the gradient eluent) to cleanly afford the title compound (4mg, 22% yield). MS (apci) m/z=602.3 (M+H).

Example 696

N-(1-(5-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

A solution of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P129; 20 mg, 0.0290 mmol),HATU (13 mg, 0.035 mmol) and 5-fluoro-2-methylbenzoic acid (4.9 mg,0.032 mmol) in DCM (579 μL) was treated with DIEA (15 μL, 0.087 mmol).The resulting mixture was stirred overnight at ambient temperature, waspurified directly by silica chromatography (using 0-10% MeOH in EtOAcwith 0.2% NH₄OH as the gradient eluent) to cleanly afford the titlecompound (4 mg, 22% yield). MS (apci) m/z=599.3 (M+H).

Example 697

tert-butyl4-(2-((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate

In a pressure tube, a mixture of tert-butyl4-(2-((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate(Intermediate P141; 50 mg, 0.10 mmol),2-chloro-N-(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Intermediate R48; 38 mg, 0.10 mmol), 2 M K₃PO_(4(aq)) (151 μL, 0.30mmol), X-phos (9.6 mg, 0.02 mmol) and Pd₂(dba)₃ (4.6 mg, 0.0050 mmol) indioxane (503 μL) was sparged with Ar_((g)) for 3 min, and then thevessel was sealed. The reaction mixture was stirred for 4 h at 80° C.After cooling to ambient temperature, the reaction mixture was dilutedwith water, and extracted with DCM (4×). The combined organic extractswere washed with brine (1×), dried over anhydrous Na₂SO_(4(s)),filtered, and concentrated in vacuo. The residue was purified twice bysilica chromatography (using 0-100% EtOAc in Hexanes then with 0-20%MeOH in DCM as the gradient eluent) to cleanly afford the title compound(2.04 mg, 2% yield). MS (apci), m/z=714.3 (M+H).

Example 698

2-chloro-N-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of tert-butyl4-(2-((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylate(Example 697; 26 mg, 0.036 mmol) in DCM (1 mL) and TFA (1 mL, 13 mmol)was stirred for 45 min at ambient temperature. The reaction mixture wastreated with saturated NaHCO_(3(aq)) (20 mL), extracted with 4:1DCM:iPrOH (3×) and eluted through a PS Frit. The organics wereconcentrated in vacuo, and the residue was purified by silicachromatography (using 0-100% DCM in Hexanes then 0-10% MeOH in DCM with0.1% NH₄OH as the gradient eluent) to cleanly afford the title compound(7 mg, 31% yield). MS (apci) m/z=614.2 (M+H).

Example 699

2-chloro-N-(1-(5-(3-cyano-6-(2-(4-ethylpiperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of2-chloro-N-(1-(5-(3-cyano-6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Example 698; 6 mg, 0.01 mmol) in DCM (488 μL) was treated withacetaldehyde (2.74 μL, 0.0488 mmol) and NaBH(AcO)₃ (20.7 mg, 0.10 mmol),then stirred for 2 d at ambient temperature. The resulting mixture waspurified directly by silica chromatography (using 0-20% MeOH in DCM with0.1% NH₄OH as the gradient eluent) to cleanly afford the title compound(1.33 mg, 20% yield). MS (apci) m/z=642.3 (M+H).

Example 700

tert-butyl3-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate

In a pressure tube, a mixture tert-butyl3-(((3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(Intermediate P144; 125 mg, 0.264 mmol),2-chloro-N-(1-(5-chloropyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Intermediate R48; 50 mg, 0.132 mmol), 2 M K₃PO_(4(aq)) (198 μL, 0.395mmol), X-phos (12.6 mg, 0.0264 mmol) and Pd₂(dba)₃ (6.04 mg, 0.00659mmol) in dioxane (659 μL) was sparged with Ar_((g)) for 10 min, and thenthe vessel was sealed. The reaction mixture was stirred overnight at 80°C. After cooling to ambient temperature, the reaction mixture wasdiluted with DCM, and extracted with water (3×) and brine (1×). Theorganic extracts were concentrated in vacuo. The residue was purified bysilica chromatography (using 0-100% EtOAc in Hexanes as the gradienteluent) to cleanly afford the title compound (28.2 mg, 31% yield). MS(apci), m/z=689.3 (M+H).

Example 701

2-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution tert-butyl3-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[15-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(Example 700; 27 mg, 0.039 mmol) in DCM (1 mL) and TFA (0.2 mL, 2.6mmol) was stirred overnight at ambient temperature. The reaction mixturewas concentrated in vacuo, and the residue was purified by silicachromatography (using 0-100% DCM/10% MeOH/1% NH₄OH as the gradienteluent) to cleanly afford the title compound (19 mg, 82% yield). MS(apci) m/z=589.2 (M+H).

Example 702

2-chloro-N-(1-(5-(3-cyano-6-((1-ethyl-3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of2-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide(Example 701; 16 mg, 0.0270 mmol) in DCM (0.15 mL) was treated withacetaldehyde (7.6 μL, 0.136 mmol) and NaBH(AcO)₃ (29 mg, 0.136 mmol),then stirred for 15 h at ambient temperature. The resulting mixture wasconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% acetonitrile in water with 0.1% TFA) to cleanlyafford the title compound (10 mg, 60% yield). MS (apci) m/z=617.2 (M+H).

Example 703

2-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamide

A solution of tert-butyl3-(((4-(5-(4-(2-chloro-5-fluorobenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(Intermediate P154; 3 mg, 0.0043 mmol) in DCM (0.25 mL) and TFA (0.05mL, 0.65 mmol) was stirred overnight at ambient temperature. Thereaction mixture was diluted with DCM, treated with saturatedNaHCO_(3(aq)), and the biphasic mixture was extracted with DCM (3×). Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo to afford the titlecompound (1.79 mg, 70% yield). MS (apci) m/z=593.2 (M+H).

Example 704

2-chloro-N-(1-(5-(3-cyano-6-((1-ethyl-3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamide

A solution of2-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamide(Example 703; 16 mg, 0.0270 mmol) in DCM (1.72 mL) was treated withacetaldehyde (7.57 μL, 0.135 mmol) and NaBH(AcO)₃ (57.2 mg, 0.270 mmol),then stirred for 1 h at ambient temperature. The resulting mixture waspurified directly by silica chromatography (using 0-20% MeOH in DCM with0.1% NH₄OH as the gradient eluent) to cleanly afford the title compound(2 mg, 12% yield). MS (apci) m/z=521.2 (M+H).

Example 705

2-chloro-N-(1-(5-(3-cyano-6-((3-fluoropyrrolidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

A solution of tert-butyl3-(((4-(5-(4-(2-chloro-6-methylbenzamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[15-a]pyridin-6-yl)oxy)methyl)-3-fluoropyrrolidine-1-carboxylate(Intermediate P149; 15 mg, 0.019 mmol) in DCM (1 mL) and TFA (1 mL, 13mmol) was stirred overnight at ambient temperature. The reaction mixturewas concentrated in vacuo, and the residue was purified directly bysilica chromatography (using 0-100% DCM in Hexanes then 0-10% MeOH inDCM with 0.1% NH₄OH as the gradient eluent to cleanly afford the titlecompound (7 mg, 60% yield). MS (apci) m/z=603.2 (M+H).

Example 706

6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a suspension of4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P42, 90 mg, 0.276 mmol) in DMSO (2 mL) was added DIEA (193μL, 1.10 mmol), followed by the addition of4-(pyridin-2-ylmethyl)piperidin-4-ol hydrochloride (69 mg, 0.303 mmol).The reaction mixture was stirred at 90° C. for 60 h, then purifieddirectly by C18 reverse phase chromatography (using 5-95% acetonitrilein water with 0.1% TFA as the gradient eluent). Fractions containing thedesired product were combined, partially concentrated in vacuo to removethe ACN, then partitioned between saturated NaHCO₃(aq) and DCM. Thebiphasic mixture was extracted with additional DCM (2×). The combinedorganic extracts were dried over anhydrous MgSO₄(s), filtered andconcentrated in vacuo. The residue was sonicated in Et₂O (2 mL) and thenconcentrated in vacuo to afford the title compound (48 mg, 35% yield).MS (apci) m/z=499.2 (M+H).

Example 707

3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)carbamate.To a mixture of 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P110, 296 mg, 0.782 mmol) and tert-butyl((3S,4S)-1-(5-chloropyrazin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Intermediate R53, 181 mg, 0.55 mmol) in dioxane (2.7 mL) was addedXPhos (52 mg, 0.11 mmol), Pd₂(dba)₃ (25 mg, 0.028 mmol), and K₃PO₄ (2 Maq., 0.82 mL). The reaction was sparged with Argon for one minute beforeheating to 85° C. and stirring overnight. After cooling to RT, thereaction was diluted with water (15 mL) and extracted with DCM (3×15mL). The combined organic extracts were washed with brine (15 mL), driedover anhydrous Na₂SO_(4(s)), filtered, and concentrated in vacuo. Thecrude material was purified by silica chromatography (0-15% MeOH/DCM) toafford the title compound (147 mg, 56% yield). MS (apci) m/z=480.2(M+H).

Step 2: Preparation of4-(5-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyrazin-2-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(147 mg, 0.31 mmol) in DCM (3 mL) and TFA (2 mL) was stirred for 30minutes at RT. The solution was concentrated in vacuo, then diluted withsaturated NaHCO₃ (10 mL) and extracted with DCM (3×10 mL). The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (58 mg, 50% yield).MS (apci) m/z=380.2 (M+H).

Step 3: Preparation of3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide.To a solution of4-(5-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyrazin-2-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(21.2 mg, 0.056 mmol) in DMSO (0.6 mL) was added 3-chloropicolinic acid(8.8 mg, 0.056 mmol) and DIEA (0.1 mL, 0.56 mmol), followed by theaddition of HATU (23.4 mg, 0.061 mmol). After stirring for 80 minutes atRT, the reaction mixture was diluted with saturated NaHCO₃ (5 mL) andextracted with DCM (3×5 mL). The combined organic extracts were washedwith brine (5 mL), dried over anhydrous Na₂SO_(4(s)), filtered, andconcentrated in vacuo to afford the title compound (29 mg, 99% yield).MS (apci) m/z=519.1 (M+H).

The compounds in Table ZZZ were prepared using a similar method asdescribed in Example 707 Step 3, replacing 3-chloropicolinic acid withthe appropriate carboxylic acid.

TABLE ZZZ MS (apci) Ex # Structure Chemical Name m/z 708

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide 464.2 (M + H) 709

2-chloro-N-((3S,4S)-1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-3-hydroxypiperidin-4-yl)-5-fluorobenzamide 536.1 (M + H) 710

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-3-hydroxypiperidin-4-yl)-3-(trifluoromethyl)- picolinamide 553.1 (M + H) 711

2-chloro-N-((3S,4S)-1-(5- (3-cyano-6- ethoxypyrazoio[1,5-a]pyridin-4-yl)pyrazin-2- yl)-3-hydroxypiperidin-4-yl)-6-fluorobenzamide 536.1 (M + H) 712

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5- a]pyridin-4-yl )pyrazin-2- yl)-3-hydroxypiperidin-4- yl)-3-methylpicolinamide  499.2,521.2 (M + H, M + Na)

Example 713

4-(6-((3r,4r)-3-amino-4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of tert-butyl((3r,4r)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)carbamate(Intermediate P158, 0.025 g, 0.052 mmol), 3-chloro-6-methylpyridazine(0.010 g, 0.078 mmol) and NaH (0.0042 g, 0.10 mmol) in DMF (0.26 mL) washeated to 90° C. overnight. The mixture was then concentrated down andpurified by preparative HPLC (5-95% ACN in water with 1% TFA). Themixture was then worked up with DCM and sat. NaHCO₃. The organic layerswere washed with brine, dried with Na₂SO₄ and concentrated to yield thetitle product (6.4 mg, 26% yield). MS (apci) m/z=471.2 (M+H).

Example 714

4-(6-((3R,4R)-3-amino-4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-((3r,4r)-3-amino-4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 713, 65 mg, 0.138 mmol) was treated with SFC chiralchromatography (5-70% MeOH:IPA:DEA 80:20:0.1) to yield two products. Thedesired product was isolated from fractions containing peak 1 and wasarbitrarily assigned as the (R,R) isomer (6.6 mg). MS (apci) m/z=471.2(M+H).

Example 715

4-(6-((3S,4S)-3-amino-4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared and purified by chiral chromatographyaccording to the procedure described in Example 714. The desired productwas isolated from fractions containing peak 2 and was arbitrarilyassigned as the (S,S) isomer (9.1 mg). MS (apci) m/z=471.2 (M+H).

Example 716

4-(6-((3r,4r)-3-amino-4-(2-isopropoxyethoxy)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of tert-butyl((3r,4r)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)carbamate(Intermediate P158, 0.035 g, 0.073 mmol), 2-(2-bromoethoxy)propane(0.012 g, 0.073 mmol) and NaH (0.0035 g, 0.088 mmol) in DMF (0.49 mL)was heated to 90° C. overnight. The mixture was concentrated andpurified by preparative HPLC (5-95% ACN in water with 1% TFA). Thefractions containing the product were concentrated and partitionedbetween DCM and sat. NaHCO₃. After phase-separation and aqueousextractions with DCM, the combined organic extracts were washed withbrine, dried with Na₂SO₄, and concentrated to yield the title product(2.9 mg, 8.5% yield). MS (apci) m/z=465.3 (M+H).

Example 717

2-chloro-N-((3R,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-5-fluorobenzamide

A mixture of4-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P159, 0.025 g, 0.0686 mmol), 2-chloro-5-fluorobenzoic acid(0.0180 g, 0.103 mmol), HATU (0.0522 g, 0.137 mmol) and Hunig's base(0.0358 ml, 0.206 mmol) in DMSO (0.686 mL) was stirred at RT overnight.The mixture was worked up with DCM and water. The organic layer waswashed with brine, dried with Na₂SO₄, filtered and concentrated. Thecrude material was purified by preparative HPLC (5-95% ACN in water with1% TFA). The combined fractions containing the product were worked upwith DCM and sat. NaHCO₃. The combined organic extracts were washed withbrine, dried (Na₂SO₄), filtered and concentrated to yield the titleproduct (0.0198 g, 55.4% yield). MS (apci) m/z=521.1 (M+H).

Example 718

2-chloro-N-((3R,4S)-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-6-fluorobenzamide

The title product was prepared according to the procedure described inExample 717, replacing 2-chloro-5-fluorobenzoic acid with2-chloro-6-fluorobenzoic acid. MS (apci) m/z=521.1 (M+H).

Example 719

N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-2-methylpropane-1-sulfonamide

A solution of4-(6-((3S,4S)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 522, Step 1; 30.6 mg, 0.0678 mmol) and2-methylpropane-1-sulfonyl chloride (15.9 mg, 0.102 mmol) in DCM (1 mL)was treated with DIEA (0.118 mL, 0.678 mmol) and stirred at RT for 1 h.The reaction mixture was treated with silica chromatography (30-100%EtOAc in hexanes) to yield the title product (12.3 mg, 36.4% yield). MS(apci) m/z=499.2, 521.2 (M+H, M+Na).

Example 720

6-ethoxy-4-(6-((3S,4S)-3-hydroxy-4-(isopentylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title product was prepared according to the procedure described inExample 719, replacing 2-methylpropane-1-sulfonyl chloride with1-bromo-3-methylbutane. The crude material was first treated with silicachromatography (0-25% MeOH in DCM), followed by preparative HPLC (15-85%ACN in water with 0.1% TFA). The combined fractions containing theproduct were partitioned between sat. NaHCO₃ and 4:1 DCM/IPA, and thecombined organic extracts were passed thru a PS-Separator frit andconcentrated to yield the title product as white solid (2.7 mg, 8%yield) MS (apci) m/z=449.3 (M+H).

Example 721

N-((3S,4S)-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide

A solution of(3S,4S)-4-amino-1-(5-(3-chloro-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-oldihydrochloride (Intermediate P161; 50 mg, 0.109 mmol) in DCM (1 mL,0.109 mmol) was treated with DIEA (0.190 mL, 1.09 mmol) and3-methylbutanoyl chloride (19.6 mg, 0.163 mmol). The reaction mixturewas stirred at rt for 1 h, then purified by silica chromatography(20-100% EtOAc in hexanes) to yield the title product as white solid(14.6 mg, 28% yield). MS (apci) m/z=472.2 (M+H).

The compounds in Table X1 were prepared using a similar method to thatdescribed in Step 2 in the synthesis ofN-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-1-(trifluoromethyl)cyclobutane-1-carboxamide(Example 522), replacing 1-(trifluoromethyl)cyclobutane-1-carboxylicacid with the appropriate carboxylic acid. Reactions were monitored forcompletion by LCMS, and reaction durations were adjusted accordingly.The title compounds were isolated following a chromatographicpurification utilizing an appropriate gradient eluent.

TABLE X1 MS (apci) Ex # Structure Chemical Name m/z 722

2-chloro-N-((3S,4S)-1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4-yl)-5-fluorobenzamide 535.2 (M + H) 723

2-chloro-N-((3S,4S)-1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4-yl)-6-fluorobenzamide 535.1 (M + H) 724

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4-yl)-3-(trifluoromethyl)- picolinamide 552.1 (M + H) 725

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4- yl)-5-fluoro-2-methylbenzamide  515.2, 557.2 (M + H, M + Na) 726

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4- yl)-3,3-difluorocyclobutane-1- carboxamide 497.2 (M + H) 727

N-((3S,4S)-1-(5-(3-cyano- 6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3-hydroxypiperidin-4- yl)-4,4,4-trifluorobutanamide 503.1 (M + H)

Example 728

N-((3r,4s)-3-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-methylbutanamide

Step 1: Preparation of(3r,4r)-3-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-ylmethanesulfonate. A mixture of tert-butyl((3r,4r)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)carbamate(Intermediate P158, 0.0234 g, 0.0489 mmol), methanesulfonyl chloride(0.00454 ml, 0.0587 mmol) and Hunig's base (0.0128 ml, 0.0733 mmol) inDCM (0.489 mL) was stirred at RT overnight. The mixture was worked upwith DCM and water. The organic layers were washed with brine, driedwith Na₂SO₄ and concentrated to yield the title compound (0.025 g, 91.9%yield). MS (apci) m/z=557.2 (M+H).

Step 2: Preparation of tert-butyl((3r,4s)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate.(3r,4r)-3-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-ylmethanesulfonate (0.025 g, 0.045 mmol) and NaN₃ (0.0035 g, 0.054 mmol)in DMF (0.45 mL) was heated to 90° C. overnight. The mixture was workedup with DCM and water. The organic layers were combined, washed withbrine, dried over Na₂SO₄, and concentrated to yield the title compound(0.021 g, 93% yield). MS (apci) m/z=504.2 (M+H).

Step 3: Preparation of tert-butyl((3r,4s)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate.Tert-butyl((3r,4s)-4-azido-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(0.021 g, 0.042 mmol) and Pd/C was stirred in MeOH under H₂ balloon for4 hours. The mixture was then filtered and concentrated down to yieldthe title compound (0.017 g, 85% yield). MS (apci) m/z=478.2 (M+H).

Step 4: Preparation ofN-((3r,4r)-3-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-methylbutanamide.A mixture of tert-butyl((3r,4s)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(0.017 g, 0.0356 mmol), 3-methylbutanoic acid (0.00545 g, 0.0534 mmol),HATU (0.0271 g, 0.0712 mmol) and Hunig's base (0.00806 mL, 0.0463 mmol)in DMSO (0.356 mL) was stirred RT overnight. The mixture was worked upwith DCM and water. The organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated, and then stirred in DCM (1 mL) andTFA (1 mL) for 1 h. The mixture was concentrated and then purified bypreparative HPLC (5-95% ACN in water with 1% TFA). The fractionscontaining the product were combined and worked up with DCM and sat.NaHCO₃. The combined organic extracts were washed with brine, dried(Na₂SO₄), filtered and concentrated to yield the title product (0.0066g, 40% yield). MS (apci) m/z=462.2 (M+H).

Example 729

N-((3S,4S)-3-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-chloropicolinamide

A mixture of tert-butyl((3S,4S)-4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate(Intermediate P162; 0.026 g, 0.0544 mmol), 3-chloropicolinic acid(0.00944 g, 0.0599 mmol), HATU (0.0414 g, 0.109 mmol) and Hunig's base(0.0123 ml, 0.0708 mmol) in DMSO (0.544 mL) was stirred at room tempovernight. The mixture was worked up with DCM and water. The organiclayer was washed with brine, dried with Na₂SO₄, filtered andconcentrated. The concentrated material was stirred in DCM (1 mL) andTFA (1 mL) for 1 h, then concentrated and purified by preparative HPLC(5-95% acetonitrile in water with 1% TFA). The fractions containing theproduct were combined and partitioned between DCM and saturated NaHCO₃The combined organic extracts were washed with brine, dried (Na₂SO₄),filtered and concentrated to yield the title product (0.008 g, 28.4%yield). MS (apci) m/z=517.2 (M+H).

The compounds in Table X2 were prepared using a similar method to thatdescribed in Example 729, replacing 3-chloropicolinic acid with theappropriate carboxylic acid. Reactions were monitored for completion byLCMS, and reaction durations were adjusted accordingly. The titlecompounds were isolated following a chromatographic purificationutilizing an appropriate gradient eluent.

TABLE X2 MS (apci) Ex # Structure Chemical Name m/z 730

N-((3S,4S)-3-amino-1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-2- chloro-6-methylbenzamide530.2 (M + H) 731

N-((3S,4S)-3-amino-1-(5- (3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-5- fluoro-2-methylbenzamide514.2 (M + H)

Example 732

N-((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamideStep 1: Preparation of4-(6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of tert-butyl((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate(Example 512; 110 mg, 0.23 mmol) in DCM (2 mL) was added TFA (1 mL).After 90 min stirring, the reaction was concentrated, taken up inminimal amount of MeOH and passed thru a P1-HCO3 resin plug. Removal ofsolvent under reduced pressure yielded the title compound, which wasdirectly used in the next step without further purifications, assumingquantitative yield. MS (apci) m/z=379.2 (M+H).

Step 2: Preparation ofN-((3R,4R)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide.A mixture of4-(6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(24 mg, 0.0634 mmol), 3-methylbutanoic acid (0.01 mL, 0.063 mmol), DCM(0.6 mL), DIEA (0.066 mL, 0.38 mmol) and HATU (29 mg, 0.076 mmol) wasstirred at RT overnight. The reaction mixture was partitioned betweenDCM and water (10 mL each). The organic layer was concentrated andpurified by preparative HPLC (5-95% acetonitrile in water with 1% TFA)to yield the title product (2 mg, 6% yield). MS (apci) m/z=463.2 (M+H).

Example 733

N-(1-(2-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-5-yl)-4-methylpiperidin-4-yl)-3-methylbutanamide

To a solution of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(P163, 4 mg, 0.00865 mmol) in DCM (0.3 mL) was added 3-methylbutanoicacid (0.001 mL, 0.013 mmol), N-ethyl-N-isopropylpropan-2-amine (0.009mL, 0.052 mmol) and HATU (4.3 mg, 0.0112 mmol). After stirred at RTovernight, the reaction was partitioned between DCM and saturatedNaHCO₃. After phase-separation, the aqueous was extracted with DCM (3×10mL). The organic extracts were combined and concentrated. The crudematerial was purified by preparative HPLC (5-95% acetonitrile in waterwith 1% TFA) to yield the title product (1.7 mg, 36%). MS (apci)m/z=547.3 (M+H).

Example 734

2-chloro-N-(1-(2-(3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-5-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

The title compound was prepared using a similar method to that describedin Example 733, replacing 3-methylbutanoic acid with the2-chloro-6-methylbenzoic acid. MS (apci) m/z=615.2 (M+H).

The compounds in Table X3 were prepared using a similar method asdescribed in Example 88, replacing 3,6-dimethylpicolinic acid with theappropriate carboxylic acid.

TABLE X3 LCMS Ex. # Structure Chemical Name m/z 735

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-4-methylpyridazine-3- carboxamide 541.2 (M + H) 736

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3-methylpyrazine-2- carboxamide 541.2 (M + H) 737

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-6-methylpyridazine-3- carboxamide 541.2 (M + H) 738

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)-3,6-dimethylpyrazine- 2-carboxamide 555.3 (M + H)

Example 739

6-ethoxy-4-(5-(4-((5-methoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(5-bromopyrimidin-2-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To (3-cyano-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-4-yl)boronicacid (Intermediate P110, 190 mg, 0.61 mmol) and 5-bromo-2-iodopyrimidine(225 mg, 0.789 mmol) in dioxane (2 mL) was added XPhos (58 mg, 0.121mmol), Pd₂(dba)₃ (3.3 mg, 0.03 mmol) and K₃PO₄ (2 M aq, 0.9 mL, 1.8mmol). The reaction mixture was sparged with argon and heated at 85° C.overnight. After cooling to RT, the reaction was partitioned in 1:1DCM:water (30 mL). After phase-separation, the aqueous was extractedwith DCM (2×15 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by silicachromatography (0-60% EtOAc/hexanes) to afford the title compound (30mg, 14%).

Step 2: Preparation of6-ethoxy-4-(5-(4-((5-methoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.A mixture of4-(5-bromopyrimidin-2-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(30 mg, 0.087 mmol), 5-methoxy-2-(piperidin-4-yloxy)pyridine (37 mg,0.18 mmol), Cs₂CO₃ (57 mg, 0.17 mmol), XPhos (4 mg, 0.0087 mmol) andPd₂(dba)₃ (4 mg, 0.0044 mmol) in dioxane (0.44 mL) was sparged withargon, and stirred at 90° C. overnight. After cooling to RT, thereaction was partitioned in 1:1 DCM:water (20 mL). Afterphase-separation, the aqueous was extracted with DCM (2×10 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by preparative TLC (10%MeOH in DCM) to afford the title product (1.4 mg, 3%). MS (apci)m/z=472.2 (M+H).

The compounds in Table X4 were prepared using a similar method asdescribed in Example 706, replacing 4-(pyridin-2-ylmethyl)piperidin-4-olhydrochloride with the appropriate piperidine intermediate.

TABLE X4 LCMS Ex. # Structure Chemical Name m/z Intermediate 740

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-(pyridin-3-ylmethyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 499.2 (M + H) 4-(pyridin-3- ylmethyl)pi- peridi 

hydrochloride (commercially available) 741

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-((6- methoxypyridin-3-yl)methyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 529.2 (M + H) R66 742

4-(6-(4-(3-fluorobenzyl)-4- hydroxypiperidin-1- yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 516.2(M + H) R67 743

4-(6-(4-((3-fluoropyridin- 2-yl)methyl)-4- hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 517.2 (M + H) R68 744

4-(6-(4-(2-fluorobenzyl)-4- hydroxypiperidin-1- yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 516.3(M + H) R55 745

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-(2-methoxybenzyl)piperidin- 1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 528.3 (M + H) R56 746

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-(3-methylbenzyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 512.3 (M + H) R62 747

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-(4-methylbenzyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 512.2 (M + H) R63 748

4-(6-(4-(4-fluorobenzyl)-4- hydroxypiperidin-1- yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 516.2(M + H) R57 749

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-(2-methylbenzyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 512.3 (M + H) R64 750

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-((6- methylpyridin-2-yl)methyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 513.2 (M + H) R58 751

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-(3-methoxybenzyl)piperidin- 1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 528.3 (M + H) R59 752

6-(2-hydroxy-2- methylpropoxy)-4-(6-(4- hydroxy-4-((5- methylpyrazin-2-yl)methyl)piperidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 514.3 (M + H) R65 753

4-(6-(4-((3-chloropyridin- 2-yl)methyl)-4- hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 533.2 (M + H) R60 754

4-(6-(4-((5-fluoropyridin- 3-yl)methyl)-4- hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 517.3 (M + H) R61

indicates data missing or illegible when filed

The compounds in Table X5 were prepared using a similar method asdescribed in Example 325, replacing 4-benzylpiperidin-4-ol with theappropriate piperidine intermediate.

TABLE X5 MS Inter- Ex. # Structure Chemical Name m/z mediate 755

6-ethoxy-4-(6-(4-hydroxy- 4-((6-methoxypyridin-3- yl)methyl)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 485.2 (M + H)R66 756

6-ethoxy-4-(6-(4-(3- fluorobenzyl)-4- hydroxypiperidin-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 472.2 (M + H) R67

The compounds in Table X6 were prepared according to the proceduredescribed in Example 415, reacting either Intermediate P80 (Method A) orIntermediate P165 (Method B) with an appropriate piperidineintermediate.

TABLE X6 MS Intermediate Ex. # Structure Chemical Name m/z (Method) 757

(R)-4-(6-(4-hydroxy-4- (pyridin-2- ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2- hydroxypropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 485.3 (M + H) 4-(pyridin-2- ylmethyl)pi- peridin-4-olhydrochloride (Commercially available) (Method A) 758

(R)-4-(6-(4-((3- fluoropyridin-2- yl)methyl)-4- hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2- hydroxypropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 503.2 (M + H) R68 (Method A) 759

(R)-4-(6-(4-((3- chloropyridin-2- yl)methyl)-4- hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2- hydroxypropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 519.1 (M + H) R60 (Method A) 760

(S)-4-(6-(4-hydroxy-4- (pyridin-2- ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2- hydroxypropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 485.2 (M + H) 4-(pyridin-2- ylmethyl)pi- peridin-4-olhydrochloride (Commercially available) (Method B) 761

(S)-4-(6-(4-((3- fluoropyridin-2- yl)methyl)-4- hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2- hydroxypropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 503.2 (M + H) R68 (Method B) 762

(S)-4-(6-(4-((3- chloropyridin-2- yl)methyl)-4- hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2- hydroxypropoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 519.2 (M + H) R60 (Method B)

Example 763

4-(5-(4-((3-chloropyridin-2-yl)methyl)-4-hydroxypiperidin-1-yl)pyrazin-2-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A pressure vessel was charged with6-(2-hydroxy-2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(P166 76.0 mg, 0.213 mmol),1-(5-chloropyrazin-2-yl)-4-((3-chloropyridin-2-yl)methyl)piperidin-4-ol(R69, 65.6 mg, 0.193 mmol), and K₃PO₄ (123 mg, 0.580 mmol), followed by1,4-dioxane (1.5 mL) and water (0.2 mL). The reaction mixture wassparged with N₂ for 10 min before Pd₂(dba)₃ (8.85 mg, 0.00967 mmol) andXPhos (18.4 mg, 0.0387 mmol) were introduced. The reaction was spargedwith N₂ for an additional 3 min before it was sealed and heated to 100°C. for 3 d to reach ˜79% conversion (LCMS). After cooling to RT, thereaction was diluted with 60/40 ACN:H₂O with 2% TFA and filtered througha Pall Acrodisc to remove solids. The filtrate was concentrated andpurified by preparative HPLC (40-60% ACN/H₂O with 0.1% TFA). Thecombined fractions containing the product were concentrated, and theresidue was taken up in MeOH and filtered through MP-HCO₃ resin. Thefiltrate was concentrated to yield the title product as yellow powder(2.0 mg, 1.9%). MS (apci) m/z=534.2 (M+H).

Example 764

3-chloro-N-(1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a mixture of 3-chloropicolinic acid (23 mg, 0.14 mmol) and HATU (37mg, 0.097 mmol) in DCM (2.4 mL) was added DIEA (84 μL, 0.48 mmol). After30-min stirring at RT,1-(5-(3-chloro-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-amine(Intermediate P175, 29 mg, 0.078 mmol) was added in one portion. Thereaction was stirred for 3 h at ambient temperature, then partitioned insat. NH₄Cl and DCM. After phase-separation, the organic layer wasconcentrated and purified by silica chromatography (0-100% EtOAc inhexanes) to afford the title product (20 mg, 50%). MS (apci) m/z=512.2(M+H).

Example 765

4-(6-(4-(fluoro(phenyl)methyl)-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (115 mg, 0.325 mmol) and V₂O₃(2.87 mg, 0.0192mmol) in CH₃CN (2 mL) was added4-(6-(4-benzyl-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 27, 95.3 mg, 0.192 mmol). The reaction mixture was frozen at−78° C., and purged of air. The mixture was slowly warmed up to RT andstirred overnight. After diluting the reaction with H₂O, the mixture wasextracted with EtOAc (3×). The combined organic extracts wereconcentrated and purified by preparative HPLC (20-80% ACN in H₂O with0.1% TFA). The combined fractions containing the product wereconcentrated, dissolved in minimal amount of MeOH, and passed throughPL-HCO3 resin. The filtrate was concentrated to afford the title productas a pale yellow solid (4.2 mg, 4%). MS (apci) m/z=516.2 (M+H).

Example 766

4-(5-(4-((3-fluoropyridin-2-yl)methyl)-4-hydroxypiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

To6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P168, 126 mg, 0.211 mmol) and1-(5-chloropyrazin-2-yl)-4-((3-fluoropyridin-2-yl)methyl)piperidin-4-ol(Intermediate R70, 68 mg, 0.211 mmol) in dioxane (1.5 mL) were addedXPhos (20 mg, 0.04 mmol), Pd₂(dba)₃ (10 mg, 0.011 mmol) and K₃PO₄ (2 Maq, 0.3 mL, 0.3 mmol). The mixture was sparged with Ar and heated to 90°C. for 17 h. After cooling to RT, the reaction was partitioned in 1:1DCM/water (30 mL). After phase-separation, the organic layer was washedwith water and brine and concentrated. The crude material was purifiedby preparative HPLC (5 to 95% acetonitrile in water with 1% TFA) toafford the title product (3.4 mg, 2.8%). MS (apci) m/z=460.2 (M+H).

The compounds in Table X7 were prepared according to the proceduredescribed in Example 766, coupling the appropriate boronate and halideintermediates.

TABLE X7 Reactant LCMS Inter- Ex. # Structure Chemical Name m/z mediates767

4-(5-(4-((3-fluoropyridin- 2-yl)methyl)-4- hydroxypiperidin-1-yl)pyrazin-2-yl)-6-(2- morpholinoethoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile 559.2 (M + H) P12  and R70 768

4-(5-(4-((3-fluoropyridin- 2-yl)methyl)-4- hydroxypiperidin-1-yl)pyrazin-2-yl)-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 518.2 (M + H) P166 and R70 769

6-(2-hydroxy-2- methylpropoxy)-4-(5-(4- hydroxy-4-(pyridin-2-ylmethyl)piperidin-1- yl)pyrazin-2- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 500.2 (M + H) P166 and R71

Example 770

(R)-N-(4-benzyl-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)piperidin-4-yl)-2,3-dihydroxypropanamideStep 1: Preparation of4-(5-(4-amino-4-benzylpiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound (62.7 mg, 53%) was prepared in the same method asdescribed in Example 766, replacing1-(5-chloropyrazin-2-yl)-4-((3-fluoropyridin-2-yl)methyl)piperidin-4-olwith 4-benzyl-1-(5-chloropyrazin-2-yl)piperidin-4-amine (IntermediateR72). LCMS m/z=440.2 (M+H).

Step 2: Preparation of(R)-N-(4-benzyl-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)piperidin-4-yl)-2,3-dihydroxypropanamide.To a mixture of D-glyceric acid hemicalcium salt (5.79 mg, 0.0396 mmol)and HATU in DMA was added N-ethyl-N-isopropylpropan-2-amine (9.19 μl,0.0528 mmol). After stirring at RT for 1 h,4-(5-(4-amino-4-benzylpiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (11.6 mg, 0.0264 mmol) was introduced and the reaction washeated at 60° C. overnight. After cooling to RT, the reaction wasdiluted with DCM, washed with water (3×) and brine (1×), thenconcentrated and purified by preparative HPLC (5-95% MeCN/H₂O/0.2% TFA).The combined fractions containing the product were concentrated, thentaken up in sat. NaHCO₃ and 4:1 DCM/IPA. The organic layer was separatedand concentrated to yield the title product (4 mg, 27%). MS (apci)m/z=528.2 (M+H).

Example 771

N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-2,3,6-trifluorobenzamide

To a mixture of 2,3,6-trifluorobenzoic acid (22 mg, 0.12 mmol) and HATU(31 mg, 0.083 mmol) in DCM (2.1 mL) was added DIEA (72 μl, 0.41 mmol)and stirred for 30 min at RT, followed by addition of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P172; 25 mg, 0.041 mmol) inone portion. After stirred for another 2 h, the reaction was dilutedwith sat. NH₄Cl (2 mL) and passed through a Phase Separator frit. Theorganic filtrate was purified by silica chromatography (0-100% EtOAc inhexanes) to afford the title compound (17 mg, 77%). MS (apci) m/z=536.1(M+H).

The compounds in Table X8 were prepared using a similar method asdescribed in Example 771, replacing 2,3,6-trifluorobenzoic acid with theappropriate carboxylic acid.

TABLE X8 LCMS Ex. # Structure Chemical Name m/z 772

2-chloro-N-(1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4- yl)-5-fluorobenzamide534.2 (M + H) 773

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4- yl)-5-fluoro-2- (trifluoromethyl)benzamide568.2 (M + H) 774

3-chloro-N-(1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4- yl)picolinamide 517.1(M + H) 775

3-chloro-N-(1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide 535.1 (M + H) 776

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4- yl)-3-fluoro-6- methylpicolinamide 515.2 (M +H) 777

3-chloro-N-(1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4-yl)-6-methylpicolinamide 531.2, 553.2  (M + H, M + Na) 778

N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4- yl)-3,6- dimethylpicolinamide 511.2 (M + H)

Example 779

2-chloro-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-6-methylbenzamide

In a 15-mL pressure tube was charged4-bromo-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate P5;15 mg, 0.056 mmol) and dioxane (0.5 mL) to form a suspension, followedby addition of water (0.15 mL), Cs₂CO₃ (55 mg, 0.17 mmol) and2-chloro-6-methyl-N-(4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperidin-4-yl)benzamide(Intermediate R49; 37 mg, 0.056 mmol). The mixture was sparged with N₂for 5 min before XPHOS (11 mg, 0.023 mmol) and Pd₂dba₃ (5.2 mg, 0.0056mmol) were added, followed by an additional 5 min of sparging with N₂before the reaction was sealed and heated at 80° C. for 17 h. Oncecooled to RT, the reaction was diluted with water (10 mL) and extractedwith DCM (2×10 mL). The combined organic phases were dried (MgSO₄),filtered, and concentrated. The crude material was purified first bypreparative HPLC (5-95% MeCN/H₂O with 0.2% TFA), followed by silicachromatography (0-100% acetone/hexanes) to afford the title product (2.1mg, 7%). MS (apci) m/z=530.2 (M+H).

The compounds in Table X9 were prepared according to the proceduredescribed in Example 779, replacing4-bromo-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile with theappropriate bromide intermediate.

TABLE X9 Bromide LCMS Inter- Ex. # Structure Chemical Name m/z mediate780*

2-chloro-N-(1-(5-(3- cyano-6-(3-hydroxy-3- methylbutoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4- yl)-6-methylbenzamide588.2 (M + H) P169 781

2-chloro-N-(1-(5-(3- cyano-6-(2-(3,3- difluoroazetidin-1-yl)ethoxy)pyrazolo[1,5- a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4- yl)-6-methylbenzamide 621.2 (M + H) P170 782

2-chloro-N-(1-(5-(3- cyano-6-(2-oxo-2- (pyrrolidin-1-yl)ethoxy)pyrazolo[1,5- a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4- yl)-6-methylbenzamide 613.2 (M + H) P171 783

2-chloro-N-(1-(5-(3- cyano-6- hydroxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4- yl)-6-methylbenzamide502.1 (M + H) P1 *Note: TBS protective group was removed duringpreparative HPLC purification (5-95% ACN in water with 0.1% TFA).

Example 784

2-chloro-N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamide

To a suspension of4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Intermediate P173; 10 mg, 0.020 mmol) in DCM (0.2 mL)were added 2-chloro-5-fluorobenzoic acid (4.2 mg, 0.024 mmol), DIEA (14μl, 0.081 mmol) and HATU (12 mg, 0.030 mmol). The reaction was stirredat RT for 2 d, then diluted with H₂O (10 mL), extracted with DCM (3×10mL), and the combined organic phases were concentrated. The crudematerial was purified by preparative HPLC (5-95% MeCN/H₂O with 0.1%TFA). The combined fractions containing the product were diluted withsat. NaHCO₃ (10 mL) and extracted with DCM (3×10 mL). The combinedorganic phases were washed with brine (15 mL), dried (MgSO₄), filtered,and concentrated to afford the title product (1.2 mg, 10%). MS (apci)m/z=578.2 (M+H).

The compounds in Table X10 were prepared using a similar method asdescribed in Example 784, replacing 2-chloro-5-fluorobenzoic acid withthe appropriate carboxylic acid.

TABLE X10 LCMS Ex. # Structure Chemical Name m/z 785

3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin- 2-yl)-4-methylpiperidin-4- yl)picolinamide561.2, 583.2  (M + H, M + Na) 786

3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin- 2-yl)-4-methylpiperidin-4-yl)-6-methylpicolinamide 575.2, 597.2  (M + H, M + Na) 787

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin- 2-yl)-4-methylpiperidin-4- yl)-2,3,6-trifluorobenzamide 580.2 (M + H) 788

3-chloro-N-(1-(5-(3- cyano-6-(2-hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin- 2-yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide 579.2 (M + H) 789

N-(1-(5-(3-cyano-6-(2- hydroxy-2- methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin- 2-yl)-4-methylpiperidin-4- yl)-5-fluoro-2-(trifluoromethyl)benzamide 612.2, 634.2  (M + H, M + Na)

Example 790

3-chloro-N-(1-(5-(3-cyano-6-((3-fluoroazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl3-(((4-(5-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[15-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate.A mixture of 3-chloropicolinic acid (24 mg, 0.15 mmol) and HATU (38 mg,0.10 mmol) in DCM (2.5 mL) was treated with DIEA (88 μL, 0.50 mmol),then stirred for 30 min at RT before tert-butyl3-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(Intermediate P153; 27 mg, 0.050 mmol) was added in one portion. Afterovernight stirring, the reaction was diluted with sat. NH₄Cl (aq) (2 mL)and passed through a Phase Separator frit. The filtrate was purified bysilica chromatography (0-100% EtOAc in hexanes) to afford the titlecompound (34 mg, quantitative yield). LCMS m/z=676.2 (M+H).

Step 2: Preparation of(R)-N-(4-benzyl-1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)piperidin-4-yl)-2,3-dihydroxypropanamide.A solution of tert-butyl3-(((4-(5-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroazetidine-1-carboxylate(34 mg, 0.050 mmol) in DCM (2 mL) was treated with TFA (2 mL). Thereaction was stirred for 20 min at ambient temperature before it wasconcentrated in vacuo and purified by silica chromatography (0-10% MeOHin DCM with 0.1% NH₄OH) to afford the title product (12 mg, 41%). MS(apci) m/z=576.2 (M+H).

Example 791

3-chloro-N-(1-(5-(3-cyano-6-methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)picolinamide

To a mixture of 3-chloropicolinic acid (15 mg, 0.096 mmol) and HATU (24mg, 0.064 mmol) in DCM (1.6 mL) was added DIEA (56 μl, 0.32 mmol), thenstirred for 30 min before4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Intermediate P174; 20 mg, 0.032 mmol) wasadded in one portion. The reaction was stirred for 1 h at RT, thendiluted with sat. NH₄Cl (aq) (2 mL) and passed through a Phase Separatorfrit. The organic filtrate was purified by silica chromatography (0-100%EtOAc in hexanes) to yield the title product as solid (14 mg, 87%). MS(apci) m/z=503.2 (M+H).

The compounds in Table X11 were prepared using a similar method asdescribed in Example 791, replacing 3-chloropicolinic acid with theappropriate carboxylic acid.

TABLE X11 LCMS Ex. # Structure Chemical Name m/z 792

3-chloro-N-(1-(5-(3- cyano-6- methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide 521.1 (M + H) 793

N-(1-(5-(3-cyano-6- methoxypyrazolo[1,5- a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4- yl)-2,3,6- trifluorobenzamide 522.1 (M + H) 794

2-chloro-N-(1-(5-(3- cyano-6- methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4- yl)-5-fluorobenzamide520.1 (M + H) 795

N-(1-(5-(3-cyano-6- methoxypyrazolo[1,5- a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4- yl)-5-fluoro-2- (trifluoromethyl)benzamide554.2 (M + H) 796

3-chloro-N-(1-(5-(3- cyano-6- methoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4-yl)-6-methylpicolinamide 517.2 (M + H)

Example 797

(R)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)picolinamide

Step 1: Preparation of tert-butyl(R)-2-(((4-(5-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate.The title compound (30 mg, 67%) was prepared according to the proceduredescribed in Example 791, replacing4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) with tert-butyl(R)-2-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate P176). LCMS m/z=688.2 (M+H).

Step 2: Preparation of(R)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)picolinamide.To a solution of tert-butyl(R)-2-(((4-(5-(4-(3-chloropicolinamido)-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(30.2 mg, 0.044 mmol) in DCM (2 mL) was added TFA (1 mL), then stirredfor 2 h at RT and then concentrated and redissolved in 4:1 DCM/IPA. Themixture was washed with sat. NaHCO₃, dried (Na₂SO₄), filtered andconcentrated to yield the title product (21.5 mg, 83% yield). MS (apci)m/z=588.3 (M+H).

The compounds in Table X12 were prepared using a similar method asdescribed in Example 797, replacing 3-chloropicolinic acid with theappropriate carboxylic acid in Step 1.

TABLE X12 LCMS Ex. # Structure Chemical Name m/z 798

(R)-3-chloro-N-(1-(5-(3- cyano-6-(morpholin-2- ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4-yl)-5-fluoropicolinamide 606.2 (M + H) 799

(R)-N-(1-(5-(3-cyano-6- (morpholin-2- ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2- yl)-4-methylpiperidin-4- yl)-5-fluoro-2-(trifluoromethyl)benzamide 639.2 (M + H)

Example 800

(S)-3-chloro-N-(1-(5-(3-cyano-6-(morpholin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)picolinamide

The title compound (50 mg, 74%) was prepared according to the proceduredescribed in Example 797, replacing tert-butyl(R)-2-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylatewith tert-butyl(S)-2-(((4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate 177). LCMS m/z=688.2 (M+H).

Example 801

(S)-4-(6-(3-(aminomethyl)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl(S)-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate

A solution of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 50.7 mg, 0.180 mmol) and tert-butyl(R)-(pyrrolidin-3-ylmethyl)carbamate (54.0 mg, 0.269 mmol) in DMSO (1.5mL) was treated with DIEA (0.157 mL, 0.898 mmol) and stirred at 1150Covernight. After cooling to RT, the reaction was diluted with H₂O andfiltered. The solid was rinsed with water, and then dried under vacuumto afford the title product as a light tan solid (83 mg, 99% yield).LCMS m/z=463.2 (M+H).

Step 2: Preparation of(S)-4-(6-(3-(aminomethyl)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl(S)-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate(83 mg, 0.18 mmol) in 1,4-dioxane (1.5 mL) was treated with conc. HCl(0.029 mL, 0.36 mmol) and stirred at RT overnight. The reaction wasconcentrated, then taken up in 4:1 DCM/IPA and free-based with sat.NaHCO₃. The organic layer was passed through a Phase-Separator frit andconcentrated to yield the title product as solid (8.9 mg, 13%). MS(apci) m/z=363.2 (M+H).

Example 802

(R)-4-(6-(3-(aminomethyl)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound (12 mg, 18%) was prepared according to the proceduredescribed in Example 801, replacing tert-butyl(R)-(pyrrolidin-3-ylmethyl)carbamate with tert-butyl(S)-(pyrrolidin-3-ylmethyl)carbamate in Step 1. LCMS m/z=363.2 (M+H).

Example 803

(S)-3-chloro-N-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)methyl)picolinamide

The title compound (32.6 mg, 71%) was prepared according to theprocedure described in Example 791, replacing4-(5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) with(S)-4-(6-(3-(aminomethyl)pyrrolidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Example 801). LCMS m/z=502.2 (M+H).

The compounds in Table X13 were prepared according to the proceduredescribed in Example 803, coupling the appropriate amine intermediatethe corresponding carboxylic acid.

TABLE X13 LCMS Amine Ex. # Structure Chemical Name m/z intermediate 804

(S)-N-((1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)methyl)- 3-methylbutanamide 447.3 (M + H) Example 801805

(R)-N-((1-(5-(3-cyano-6- ethoxypyrazolo[1,5- a]pyridin-4-yl)pyridin-2-yl)pyrrolidin-3-yl)methyl)- 3-methylbutanamide 447.3 (M + H) Example 802806

(R)-3-chloro-N-((1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)pyrrolidin-3- yl)methyl)picolinamide 502.1(M + H) Example 802

Example 807

N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-2-hydroxyacetamideStep 1: Preparation of4-(6-(4-amino-4-benzylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl 4-amino-4-benzylpiperidine-1-carboxylate (220mg, 0.758 mmol) in DCM (1.5 mL) was treated with TFA (0.5 mL), stirredat RT for 1 h then concentrated. The residue was re-dissolved in DMA(3.8 mL), followed by addition of6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6, 214 mg, 0.758 mmol) and K₂CO₃ (524 mg, 3.79 mmol). Themixture was stirred at 60° C. for 24 h before it was cooled to RT anddiluted with water. The aqueous mixture was extracted with EtOAc, andthe combined organic extractions was concentrated and purified by silicachromatography (0-100% DCM/10% MeOH/1% NH₄OH) to yield the titlecompound (261 mg, 76%). LCMS m/z=453.2 (M+H).

Step 2: Preparation ofN-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-2-hydroxyacetamide

To a solution of4-(6-(4-amino-4-benzylpiperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile(30 mg, 0.0663 mmol) in DCM (0.66 mL) was added 2-hydroxyacetic acid(5.55 mg, 0.0729 mmol), N— ethyl-N-isopropylpropan-2-amine (23.1 μl,0.133 mmol), and HATU (30.2 mg, 0.0795 mmol), then stirred at RTovernight. The reaction mixture was directly treated with reverse phasechromatography (5-95% MeCN/H₂O/0.2% TFA). The combined fractionscontaining the product were partitioned between 4:1 DCM/IPA and sat.NaHCO₃. After phase-separation the organic layer was concentrated toyield the title product as solid (7.2 mg, 21%). MS (apci) m/z=511.2(M+H).

The compounds in Table X14 were prepared using a similar method asdescribed in Step 2 of Example 807, replacing 2-hydroxyacetic acid withthe appropriate carboxylic acid.

TABLE X14 LCMS Ex. # Structure Chemical Name m/z 808

(S)-N-(4-benzyl-1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-3- hydroxybutanamide 539.2(M + H) 809

(S)-N-(4-benzyl-1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-2- hydroxypropanamide 525.3(M + H) 810

(R)-N-(4-benzyl-1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-2- methoxypropanamide 539.3(M + H) 811

(R)-N-(4-benzyl-1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-1- methylpyrrolidine-2-carboxamide 564.3 (M + H) 812

N-(4-benzyl-1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-2- hydroxy-2-methylpropanamide 539.2 (M + H) 813

(R)-N-(4-benzyl-1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-2,3- dihydroxypropanamide541.2 (M + H) 814

N-(4-benzyl-1-(5-(3- cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperidin-4-yl)-2- (dimethylamino)acetamide538.2 (M + H)

Example 815

(2S,3R)-2-amino-N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-hydroxybutanamide

The title compound was prepared using a similar method as described inStep 2 of Example 807, replacing 2-hydroxyacetic acid with anN-Fmoc-protected acid (((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine.The N-protected crude product was treated with 1:1 morpholine:DCM toremove the protective group, then concentrated and purified according tothe procedure described in Example 807 to afford the final product assolid (13.8 mg, 28%). MS (apci) m/z=554.3 (M+H).

Example 816

(S)-2-amino-N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-methylbutanamide

The title compound (3 mg, 8%) was prepared using a similar method asdescribed in Example 815, replacing(((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine with(((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine. MS (apci) m/z=552.3(M+H).

Example 817

(2S,3S)-N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidine-2-carboxamide

The title compound was prepared using a similar method as described inStep 2 of Example 807, replacing 2-hydroxyacetic acid with anN-Boc-protected acid(2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid.The N-protected product was isolated after a silica chromatography(0-100% EtOAc in hexanes). The isolated product was dissolved in 1:1DCM:TFA at 0° C., then allowed to slowly warm up to RT over 24 h. Afterremoval of solvent, The crude material was treated with a second silicachromatography (0-100% 1:9 MeOH:DCM with 1% NH₄OH in DCM) to afford thetitle product as solid (33 mg, 36%). MS (apci) m/z=566.2 (M+H).

Example 818

(2S,3S)-N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-1-ethyl-3-hydroxypyrrolidine-2-carboxamide

A solution of (2S,3S)-N-(4-benzyl-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidine-2-carboxamide(Example 817, 15 mg, 0.0265 mmol) in DCM (0.13 mL) was treated withsodium triacetoxyhydroborate (11.2 mg, 0.0530 mmol) and acetaldehyde(0.769 μL, 0.0265 mmol), then stirred at RT overnight. The reactionmixture was diluted with 4:1 DCM/IPA and washed with sat. NaHCO₃ (aq).After phase separation, the organic layer was concentrated to yield thetitle product (11 mg, 72%). MS (apci) m/z=594.3 (M+H).

Example 819

(R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-ylmethyl)piperidin-4-yl)-2,3-dihydroxypropanamide

The title product (21.6 mg, 18%) was prepared using a similar method asdescribed in Step 1 of Example 626, replacing2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid with D(+)-glycericacid hemicalcium salt. MS (apci) m/z=542.2 (M+H).

Abbreviations: 18-Crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane ACNAcetonitrile AcOH Acetic Acid (±)-BINAP2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene Bis(pinacolato)diboron4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) Boctert-butyl carboxylate group Boc-anhydride di-tert-butyl dicarbonateBoc-Inp-OH 1-Boc-piperidine-4-carboxylic acid; or Boc-isonipecotic acidn-BuLi n-butyllithium or 1-butyllithium s-BuOH Sec-Butanol or 2-Butanolt-BuOH tert-Butanol or 2-Methylpropan-2-ol Celite ® Diatomaceous earth;SiO₂ CuI Copper (I) iodide Cu(OAc)₂ Copper (II) diacetate d day, daysDCE 1,2-Dichloroethane DCM Dichloromethane DIAD Diisopropylazodicarboxylate DIEA N,N-Diisopropylethylamine DI water Deionized waterdioxane 1,4-dioxane DMA N,N-Dimethylacetamide DMAP4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DMFN,N-Dimethylformamide DMSO Dimethylsulfoxide DMP Dess-MartinPeriodinane;1,1,1-Tris(acetyloxy)-1,1-dihydro- 1,2-benziodoxol-3-(1H)-one EDC-HCl1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Et₂O DiethylEther EtOAc Ethyl Acetate EtOH Ethanol eq equivalent GF/F paper GF/Fglass microfiber filter paper h hour, hours HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxide hexafluorophosphate or 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxidehexafluorophosphate or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOAc Acetic Acid isobutylchloroformate isobutyl carbonochloridate isovaleryl chloride3-methylbutanoyl chloride iPrOH Isopropanol i-PrMgCl Isopropyl magnesiumchloride KOAc Potassium Acetate KOtBu Potassium tert-Butoxide K₂HPO₄Potassium Phosphate, Dibasic LCMS Liquid chromatography-massspectrometry LiHMDS Lithium Hexamethyldisilazide; or Lithiumbis(trimethylsilyl)amide MeOH Methanol Me₄N(AcO)₃BH TetramethylammoniumTriacetoxyborohydride min minute, minutes MSHo-(mesitylsulfonyl)hydroxylamine MTBE Methyl tert-Butyl Ether NCSN-Chlorosuccinimide NBS N-Bromosuccinimide NIS N-IodosuccinimideNaBH(AcO)₃ Sodium Triacetoxyborohydride NH₄OAc Ammonium Acetate P1-HCO₃resin Stratospheres MP-HCO3 10% Pd/C Palladium 10 wt. % (dry basis),active carbon, wet, Degussa Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium (0) Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium (0) PdCl₂(dppf)•CH₂Cl₂1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex Pd₂(dba)₃•CHCl₃tris(dibenzylideneacetone)dipalladium (0) chloroform complexPdCl₂(PPh₃)₂ Palladium(II)bis(triphenylphosphine) dichloride, PPh₃Triphenylphosphine PPTS Pyridinium p-toluenesulfonate PS frit Biotage ®“Isolute ® Phase Separators” PS paper Whatman ® silicone treated PhaseSeparators filter paper PVDF (0.45 μm) disc polyvinylidene difluoridemembrane with a 0.45-micron pore size rt Room temperature TBAFTetra-n-butylammonium fluoride TEA Triethylamine TFA Trifluoroaceticacid THF tetrahydrofuran Triphosgene (bis(trichloromethyl) carbonateTf-O-Tf trifluoromethanesulfonic anhydride TsCl 4-Toluenesulfonylchloride X-Phos dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine

What is claimed is:
 1. A compound of the Formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein: X¹,X², X³ and X⁴ are independently CH, CCH₃, CF or N, wherein zero, one ortwo of X¹, X², X³ and X⁴ is N; A is H, Cl, methyl, ethyl or cyclopropyl;B is: (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1-3fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionallysubstituted with a C3-C6 cycloalkylidene ring, (d) dihydroxyC3-C6 alkyl-wherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring, (e) (C1-C6 alkoxy)C1-C6 alkyl- optionallysubstituted with 1-3 fluoros, (f) (R¹R²N)C1-C6 alkyl- where R¹ and R²are independently selected from H, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(═O)—;(g) hetAr¹C1-C3 alkyl-, where hetAr¹ is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andis optionally substituted with one or more independently selected C1-C6alkyl substituents; (h) (C3-C6 cycloalkyl)C1-C3 alkyl-, (i)(hetCyc^(a))C1-C3 alkyl-, (j) hetCyc^(a), (k) (R¹R²N)C(═O)C1-C6 alkyl-where R¹ and R² are independently selected from H and C1-C6 alkyl, (l)(R¹R²N)C(═O)—, where R¹ and R² are independently selected from H andC1-C6 alkyl, or (m) hetCyc^(a)C(═O)C1-C6 alkyl-; hetCyc^(a) is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O and optionally substituted with one or moresubstituents independently selected from OH, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl, halogen, (C1-C6alkyl)C(═O)—, C1-C6 alkoxy, oxo, and (C1-C6 alkoxy)C(═O)—; Ring D is (i)a saturated monocyclic 4-7 membered heterocyclic ring having one ringheteroatom which is nitrogen, (ii) a saturated 7-8 membered bridgedheterocyclic ring having one ring heteroatom which is nitrogen, or (iii)a saturated 7-11 membered heterospirocyclic ring system having one ringheteroatom which is nitrogen; each R^(a) is independently C1-C6 alkyl(optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl or (C1-C6alkoxy)C1-C6 alkyl-; R^(b) is (a) hydroxy, (b) cyclopropyl, (c)hetCyc^(b)CH₂—, (d) R^(i)R^(j)NC(═O)CH₂OCH₂— where R^(i) and R areindependently H or C1-C6 alkyl, (e) R^(c)R^(d)N—, (f) R^(c)R^(d)NCH₂—,(g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portionis optionally substituted with hetCyc^(b), hetAr^(a), C1-C6 alkoxy- orR′R″N—, or said alkyl portion is optionally substituted with twosubstituents independently selected from R′R″N— and OH, where each R′and R″ is independently hydrogen or C1-C6 alkyl, (i) (R′R″N)C1-C6alkoxy(CH₂)_(n)— where n is 0 or 1 and R′ and R″ are independentlyhydrogen or C1-C6 alkyl, (j) hetCyc^(b)(C1-C3 alkyl)OCH₂—, (k)hetCyc^(b)C(═O)NH— or (l) hetAr^(a)C(═O)NH—; hetCyc^(b) is a 4-6membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, ora 7-10 membered heterospirocyclic ring, each ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc^(b) isoptionally substituted with one or more substituents independentlyselected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl- (optionally substituted with 1-3 fluoros),(C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkoxy)C(═O)—, C1-C6 alkoxy, andR′R″N— where R′ and R″ are independently hydrogen or C1-C6 alkyl;hetAr^(a) is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S herein hetAr^(a) is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3fluoros); R^(c) is hydrogen or C1-C6 alkyl; R^(d) is hydrogen, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O)—,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyC1-C6 alkyl)C(═O)—, (C1-C6 alkyl)C(═O)—, (R^(k)R^(l)N)C1-C6alkyl- where R^(k) and R^(l) are independently H or C1-C6 alkyl,R^(m)R^(n)NC(═O)C1-C6 alkyl- where R^(m) and R^(n) are independently Hor C1-C6 alkyl, PhCH₂— wherein the phenyl is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6cycloalkyl, hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO₂—, R^(e)R^(f)N— and(R^(e)R^(f)N)C1-C6 alkyl- where each R^(e) and R^(f) is independently Hor C1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl-, or hetCyc^(c) wherehetCyc^(c) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O and optionally substituted with C1-C6 alkyl; n is0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; E is: (a) hydrogen, (b) hydroxy, (c)C1-C6 alkyl optionally substituted with 1-3 fluoros, (d) Ar¹C1-C6 alkyl-wherein said alkyl portion is optionally substituted with 1-3 fluoros,(e) hetAr²C1-C6 alkyl-, (f) (C1-C6 alkoxy)C1-C6 alkoxy-, (g) Ar¹O—, (h)hetAr²—O—, (i) Ar¹NR^(g)— where R^(g) is H or C1-C6 alkyl, (j)hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl, (k) R³C(═O)NR^(g)— whereR^(g) is H or C1-C6 alkyl; (l) Ar¹C(═O)NR^(g)— where R^(g) is H or C1-C6alkyl, (m) hetAr²C(═O)NR^(g) (CH₂)_(p)— where p is 0 or 1 and R^(g) is Hor C1-C6 alkyl, (n) R⁴R⁵NC(═O)—, (o) Ar¹NR^(g)C(═O)—, where R^(g) is Hor C1-C6 alkyl, (p) hetAr²NR^(g)C(═O)—, where R^(g) is H or C1-C6 alkyl,(q) Ar¹(C1-C6 alkyl)C(═O)— wherein said alkyl portion is optionallysubstituted with OH, hydroxy(C1-C6 alkyl), C1-C6 alkoxy or NH₂, (r)hetCyc⁵C(═O)—, (s) R⁴R⁵NC(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,(t) (C1-C6 alkyl)SO₂—, (u) Ar¹(C1-C6 alkyl)C(═O)NR^(g)— where R^(g) is Hor C1-C6 alkyl, (v) hetAr⁴C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl,(w) hetAr²—S(═O)—, (x) (C3-C6 cycloalkyl)CH₂SO₂—, (y) Ar¹(C1-C6alkyl)SO₂—, (z) hetAr²SO₂—, (aa) Ar¹, (bb) hetAr², (cc) hetCyc⁵, (dd)C1-C6 alkoxy, (ee) Ar¹(C1-C6 alkyl)-O—, (ff) hetAr²(C1-C6 alkyl)-O—,(gg) hetAr²—O—C1-C6 alkyl-, (hh) Ar¹(C1-C6 alkyl)NR^(g)— where R^(g) isH or C1-C6 alkyl, (ii) hetAr²—S—, (jj) Ar²SO₂NR(CH₂)_(p)— where p is 0or 1 and R^(g) is H or C1-C6 alkyl, (kk) (C1-C6 alkoxy)C(═O)—, (ll)(C1-C6 alkyl)NR^(g)C(═O)O— where R^(g) is H or C1-C6 alkyl, (mm) (C1-C6alkyl)NR^(g) SO₂— where R^(g) is H or C1-C6 alkyl, (nn)hetCyc⁵C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, (oo) Q-NR^(h)(C1-C3alkyl)C(═O)NR^(g)— where R^(g) and R^(h) are independently H or C1-C6alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,

 where R^(g) and R^(h) are independently H or C1-C6 alkyl, Q is H, C1-C6alkyl or (C1-C6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,

 where R^(g) and R^(h) are independently H or C1-C6 alkyl and Q is H,C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,

 where R^(g) is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6alkyl)OC(═O)—, (ss) R^(g)R^(h)N— where R^(g) and R^(h) are independentlyH or C1-C6 alkyl, (tt) (C3-C6 cycloalkyl)C(═O)NR^(g)— where thecycloalkyl is optionally and independently substituted with one or morehalogens, (uu) (C1-C6 alkyl)C(═O)NR^(g)CH₂— where R^(g) is H or C1-C6alkyl, or (vv) C1-C6 alkyl)SO₂NR^(g)— where R^(g) is H or C1-C6 alkyl;Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, C1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl,hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO₂—, R^(e)R^(f)N— and(R^(e)R^(f)N)C1-C6 alkyl- where each R^(e) and R^(f) is independently Hor C1-C6 alkyl; hetAr² is a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S, or a 9-10 memberedbicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr² isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionallysubstituted with 1-3 fluoros) and hydroxyC1-C6 alkoxy-; hetCyc⁵ is a 4-6membered saturated heterocyclic ring having 1-2 ring heteroatomsindependently selected from N, O and S wherein said heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from C1-C6 alkoxy and oxo; R³ is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, C3-C6cycloalkyl, (C3-C6 cycloalkyl)CH₂—, (C3-C6 cycloalkyl)O—, (C3-C6cycloalkyl)CH₂O—, hetCyc⁷O—, Ph-O—, or (C1-C6 alkoxy)C1-C6 alkyl-;wherein each of said C3-C6 cycloalkyl moieties is optionally substitutedwith C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6alkoxy, OH, or R′R″N— where R′ and R″ are independently hydrogen orC1-C6 alkyl; R⁴ is H or C1-C6 alkyl; R⁵ is Ar², hetAr³, Ar²CH₂—,hetCyc⁶-CH₂—, hydroxyC1-C6 alkyl-, (C3-C6 cycloalkyl)CH₂—, or C1-C6alkyl optionally substituted with 1-3 fluoros; Ar² is phenyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3fluoros), C3-C6 cycloalkyl, and R^(g)R^(h)N— where R^(g) and R^(h) areindependently H or C1-C6 alkyl, or Ar² is phenyl fused to a 6 memberedheterocyclic ring having a ring nitrogen atom and optionally substitutedwith C1-C6 alkyl; hetAr³ is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, O and S and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, CN, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3fluoros), and (C1-C6 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3fluoros); hetAr⁴ is pyridin-4(1H)-onyl or pyridin-2(1H)-onyl optionallysubstituted with one or more substituents independently selected fromC1-C6 alkyl and halogen; hetCyc⁶ is a 5-7 membered heterocyclic ringhaving 1-3 ring heteroatoms independently selected from N, O and S; andhetCyc⁷ is a 5-7 membered heterocyclic ring having 1-3 ring heteroatomsindependently selected from N, O and S.
 2. A compound according to claim1, wherein D is a saturated monocyclic 4-7 membered heterocyclic ringhaving one ring heteroatom which is nitrogen.
 3. A compound according toclaim 1, wherein n is 0 or
 1. 4. A compound according to claim 1,wherein E is (a) hydrogen, (b) hydroxy, (c) C1-C6 alkyl optionallysubstituted with 1-3 fluoros, (d) Ar¹C1-C6 alkyl- wherein said alkylportion is optionally substituted with 1-3 fluoros, (e) hetAr²C1-C6alkyl-, (g) Ar¹O—, (h) hetAr²O—, (i) Ar¹NR^(g)— where R^(g) is H orC1-C6 alkyl, (j) hetAr²NR^(g)— where R^(g) is H or C1-C6 alkyl, (k)R³C(═O)NR^(g)— where R^(g) is H or C1-C6 alkyl, (l) Ar¹C(═O)NR^(g)—where R^(g) is H or C1-C6 alkyl, (m) hetAr²C(═O)NR^(g) (CH₂)_(p)— wherep is 0 or 1, (n) R⁴R⁵NC(═O)—, or (s) R⁴R⁵NC(═O)NR^(g)— where R^(g) is Hor C1-C6 alkyl.
 5. A compound according to claim 1, wherein B is C1-C6alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkylwherein the alkyl portion is optionally substituted with a C3-C6cycloalkylidene ring.
 6. A compound according to claim 1, wherein thecompound is

or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition, comprising a compound according to claim 1 in admixturewith a pharmaceutically acceptable diluent or carrier.
 8. A method fortreating cancer in a patient in need thereof, the method comprisingadministering to the patient an effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 9. The method of claim8, wherein the cancer is a RET-associated cancer.
 10. The method ofclaim 9, wherein the RET-associated cancer is selected from the groupconsisting of: lung cancer, papillary thyroid cancer, medullary thyroidcancer, differentiated thyroid cancer, recurrent thyroid cancer,refractory differentiated thyroid cancer, multiple endocrine neoplasiatype 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma,parathyroid hyperplasia, breast cancer, colorectal cancer, papillaryrenal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa,and cervical cancer.
 11. The method of claim 10, wherein theRET-associated cancer is medullary thyroid cancer.
 12. The method ofclaim 10, wherein the RET-associated cancer is lung cancer and the lungcancer is small cell lung carcinoma, non-small cell lung cancer,bronchioles lung cell carcinoma, RET fusion lung cancer, or lungadenocarcinoma.
 13. The method of claim 12, wherein the lung cancer isRET fusion lung cancer.
 14. The method of claim 8, further comprisingadministering one or more additional therapies or therapeutic agents tothe patient.
 15. The method according to claim 14, wherein said one ormore additional therapies or therapeutic agents is radiotherapy,cytotoxic chemotherapeutics, kinase targeted-therapeutics, apoptosismodulators, signal transduction inhibitors, immune-targeted therapies,or angiogenesis-targeted therapies.